Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes

Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes Pål Møller, Saski Haupt, Aysel Ahadova, Matthias Kloor, Julian Sampson, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4238470/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database [PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair [ path_MMR ) genes. Material and methods: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. Results: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. Conclusions: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. The findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing adenomas which might otherwise become CRCs. However, in carriers other than path_PMS2 , most CRCs observed in carriers subjected to colonoscopy likely arise from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. This mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports. MSI MLH1 MSH2 MSH6 PMS2 dMMR Lynch syndromes colorectal cancer adenoma colonoscopy sojourn time Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background There are four dominantly inherited microsatellite instability (MSI) Lynch syndromes, caused by pathogenic variants of the four MMR (path_MMR) genes MLH1, MSH2, MSH6 and PMS2 (OMIM # 120435; # 609310; #614350 and #614337) [1, 2]. Deletions of the EPCAM tail #613244 epigenetically silence the MSH2 gene and in this report are grouped together with OMIM # 120435. The four path_MMR variant groups have different penetrance (incidence of any cancer) and expressivities (incidences of cancer in the different affected organs), causing different overall risks of death related to any cancer and to cancer in specific organs [1]. CRC in the normal population is assumed to most often arise through biallelic somatic APC mutations initiating an adenoma that may develop into a CRC as a result of acquiring additional driver mutations, and less often through an initiating CTNNB1 mutation [3, 4]. Assuming that CRCs in path_MMR carriers develop from adenomas, and observing that carriers do not have many adenomas, the paradigm of an accelerated adenoma-carcinoma pathway was established in the Lynch syndromes [5]. The mechanism for the accelerated pathway was assumed to be mediated via deficiency of MMR proteins (dMMR) in MSI adenomas [6]. It soon became clear that colonoscopy with polypectomy (below referred to as colonoscopy) every third year did not prevent CRC in carriers as had been hoped and more frequent colonoscopies were advocated [7]. However, large studies reported that shorter intervals between colonoscopies reduced neither CRC incidences in path_MMR carriers nor its stage at diagnosis [8, 9]. To assess the incidence and prognosis of CRC in path_MMR carriers subjected to colonoscopy as is advocated in clinical guidance, the European Hereditary Tumour Group (EHTG, www.ehtg.org, at that time named The Mallorca Group) initiated the Prospective Lynch Syndrome Database (PLSD, www.plsd.eu ). When comparing CRC incidences in carriers followed up in PLSD who were subjected to colonoscopy surveillance with other cohorts of carriers who did not all receive colonoscopy surveillance, the CRC incidences in path_MLH1, path_MSH2 and path_MSH6 carriers were either increased or not reduced in PLSD, depending on which retrospective segregation analyses were used in the comparator groups [10–13]. By contrast, CRC incidences in path_PMS2 carriers followed up in PLSD were reduced [14]. A recent position statement by the EHTG discusses that these findings may be in keeping with emerging knowledge that adult path_MLH1 and path_MSH2 carriers have huge numbers of MMR-deficient crypts (dMMR) arising in their colons [15-17]. It appears that these may be controlled or destroyed by the immune system or may develop into CRC without an intermediate adenoma stage. Further, it is now also clear that not only dMMR crypts, but also dMMR/MSI CRCs may be removed by the host immune system, as demonstrated by the success of immune checkpoint blockade therapy [1, 18, 19]. Previous studies using the PLSD have provided new data and insights into the associations between colonoscopy intervals, incidences of CRC by age and times from a normal surveillance colonoscopy to diagnosis of CRC, its stage at diagnosis and prognosis. In this report we add new data on the incidences of colorectal adenomas and their relationship to the incidences of CRC. Aims The aims were to determine the incidences of colorectal adenomas by age and gene in path_MMR carriers, compare these with the incidences of CRC and evaluate the results in relation to previously reported paradigms [5, 3] and our previously suggested hypotheses regarding pathways to CRC in the Lynch syndromes [1, 6, 20] thereby better informing future clinical guidelines for prevention and treatment. Materials and methods The PLSD was initiated in 2012 and the first report on CRC incidences, stratified by MMR gene was published in 2015 [21]. Since then, the number of individuals under follow up in PLSD has tripled, while the incidences of CRC by age, gene and gender have remained similar, leading us to conclude that the incidences have been validated in the newly recruited cases. The methods used and our most recent results have been described in detail [1,22-24] (www.plsd.eu). In the current study, as detailed in our previous reports, cumulative incidences of CRC were calculated from 25 to 75 years of age as time to first CRC in carriers who had not had CRC prior to or at their first prospectively planned and completed colonoscopy. Overall 10 year survival following CRC was estimated. Polyps were grouped as adenomas or non-adenomatous polyps, and adenomas were grouped as either advanced or not (advanced adenomas = those >10mm diameter and/or villous morphology and/or high grade dysplasia). The total number of adenomas removed up to and including at the last colonoscopy was noted for each path_MMR carrier. We compared incidences of adenomas by age and gene using standard linear regression analysis. We also report on the presence or absence of adenomas at the last colonoscopy undertaken before CRC was diagnosed and the time between that last colonoscopy and the diagnosis of CRC. Carriers were grouped into those who had ever had adenoma(s) and those who had not and cumulative incidences of CRC were compared, stratified by age and by gene. We discuss the results using the concept of mean sojourn time which makes no assumptions regarding mechanisms for what is observed [25], as is usual when examining the effectiveness of screening in cancer prevention. This may be explained as follows: ‘ The parameter estimated in practice in screening programs is the average sojourn time over all disease cases, usually referred to as the mean sojourn time. A long mean sojourn time indicates a good potential for screening. The shorter the sojourn time, the more frequently screening has to take place in order to be effective. If the mean sojourn time is very short, screening may not be worthwhile at all .’ [26]. Screening colonoscopy to prevent CRC is based on the adenoma-carcinoma paradigm [5] with detection and removal of tumours at the adenoma stage. Here we consider sojourn time as the time for which the tumour is detectable as an adenoma by colonoscopy. PLSD records discrete observations in time that are assumed to be Poisson-distributed [27] and that may be considered based on the paradigm of stochastic causative processes [28, 29] Results The required details were available for 3,574 carriers who were followed for 38,735 years after their initial (prevalence) colonoscopies. The mean ages of male and female carriers in each path_MMR group were similar at the end of the study (range 52.8 to 57.0 years, see details in Table 1). 2,444 (68%) had never had a colorectal adenoma detected at colonoscopy and 1,130 (32%) had one or more colorectal adenomas detected, all of which were removed. The detailed findings, grouping carriers by gene, their total number of adenomas (advanced and not advanced) and the numbers of non-adenomatous polyps (categorised as unclassified, hyperplastic, serrated, juvenile or hamartomatous), total number of polyps and average age in each group are given in Table 2. The numbers in Table 2 are illustrated as pie-charts of the number of adenomas in carriers by gene in Figure 1, and as results of standard linear regression of the number of adenomas by carrier and by gene in Figure 2. Annual incidences of both CRC and colorectal adenomas increased with age (Table 2 and Figure 3) as previously reported by others [30]. There was no statistically significant difference in the prevalence of adenomas in path_MLH1 versus path_MSH2 carriers but both path_MSH6 and path_ PMS2 carriers were significantly less likely to have any adenomas than were path_MLH1 or path_MSH2 carriers (p<0.001). In contrast, among carriers with adenomas path_MLH1 , path_MSH2 and path_MSH6 carriers all had similar regression curves for numbers of adenomas, while path_PMS2 carriers less frequently had multiple adenomas (Figure 2 and Figure 3, p<0.01). Advanced adenomas were with one exception seen only in carriers with multiple adenomas. Serrated adenomas were rarely seen (Table 2). If, as we propose, adenomas may disappear spontaneously in path_MMR carriers because of targeting by the host immune system, the cumulative incidences of adenomas shown in Figure 3 may be underestimates. As seen in Table 2, 34%, 34%, 27% and 21% of path_MLH1 , path_MSH2, path_MSH6 and path_PMS2 carriers had one or more adenomas and only 5%, 7%, 5% and 4%, respectively, had more than 3 adenomas. There were therefore insufficient numbers to calculate meaningful cumulative incidences of CRC by age in carriers with multiple adenomas. Among the 3,574 carriers included in the study, 2,293 (64%) had no CRC before or at the first planned and carried out (prevalence round) colonoscopy. They were followed-up with regular colonoscopy for 26,213 years and 239 CRCs were diagnosed prospectively in carriers from 25 to 75 years of age. Details are given in Table 3. These included 151, 85, 12 and 1 CRCs in carriers of path_MLH1, path_MSH2, path_MSH6 and path_PMS2 , respectively. Table 4 shows the numbers of carriers with and without adenomas at the last colonoscopy before diagnosis of CRC, together with the number of months elapsed between the last colonoscopy and diagnosis of CRC. In each group of path_MMR carriers, the majority had no adenomas at the last colonoscopy and the months elapsed were similar in carriers with and without adenomas. As seen in Figure 3, there were no differences in the cumulative incidences of CRC by gene in path_MLH1, path_MSH2 and path_MSH6 carriers stratified by the presence or absence of adenomas (the curves are overlapping and no confidence estimates or calculation of p-values were needed to reach this conclusion). No CRC was diagnosed prospectively in path_PMS2 carriers below 75 years of age. There was no significant difference in 10-year overall survival after first prospectively detected CRC in carriers with and without adenomas (88% and 81%, p>0.05 respectively). Discussion The findings of this study are that 1) the majority of path_MMR carriers did not develop any colorectal adenoma(s) during follow up, 2) colonoscopy appeared to prevent CRC in path_PMS2 carriers but not in the others, and 3) there was no association between the incidences of adenomas and CRCs in any group of carriers. In contrast to previous reports on carriers not subjected to colonoscopy [14], no CRC was diagnosed prospectively in path_PMS2 carriers below 75 years of age, to the combined conclusion that colonoscopy as undertaken had prevented CRC in path_PMS2 carriers in the current study. The lower incidences of colorectal adenomas in path_PMS2 carriers compared to path_MLH1, path_MSH2 and path_MSH6 carriers, may suggest that some adenomas in the latter groups are attributable to the path_MMR genotypes. Considered in relation to the sojourn time paradigm, the PLSD findings are in keeping with a theory that colonoscopy blocks the adenoma-carcinoma pathway and that the CRCs observed had no or short sojourn times as adenomas. CRCs arising by the CTNNB1 pathway appear to have no sojourn time as adenomas [3], are not frequent in path_MMR carriers [31], and may be specific for path_MMR carriers [32-34]. Our findings pose the following question: if the adenoma-carcinoma pathway that is initiated by APC mutation [3, 6, 31] is blocked by colonoscopy and the carcinogenetic pathway has to include an early mutation causing an increased cell proliferation rate [3, 20], how have the observed CRCs emerged? There are many published pathophysiological, biochemical and DNA analyses of adenomas and CRCs. Based on these, we have suggested an additional pathway in path_MMR carriers in which dMMR crypts may trigger the adenoma-carcinoma pathway [6]. A recent mathematical analysis of the most frequently mutated genes in CRCs supported this theory [20]. Descriptions of tumours reflect different time-points in different carcinogenetic processes and, when tumours are removed for observation, subsequent events that might have occurred are blocked (“ the very act of measurement or observation directly alters the phenomenon under investigation”) [35]. In relation to the adenoma-carcinoma sequence, there would be obvious ethical problems with any study proposing to observe the transition of adenomas to CRCs in humans and, in addition, there is no way of fully characterising an adenoma or CRC without altering it. As no direct observations of the order of events in carcinogenetic processes are possible, the suggested linear models that are based on biological findings in adenomas and CRCs are assumed, not observed. In addition, mutations observed in adenomas and CRCs are influenced by selection (in path_MMR carriers including survival in the face of the host immune system’s continuous efforts to identify and remove the tumours) and genetic drift which may involve interacting stochastic processes. When re-examining the arguments for our previous suggestion of three linear pathways to CRC in path_MMR carriers [6] and adding the findings reported in this paper, we conclude that the following model is probable: The main pathway to CRC in path_MMR carriers may be triggered by a second-hit in the wild-type MMR allele leading to a dMMR crypt and increasing the acquisition of mutations in driver genes [3, 20] in a continuous chaotic stochastic process which may lead to CRC. The probability of any one dMMR clone leading to CRC seems to be very low. Adult path_MLH1 and path_MSH2 carriers have thousands of dMMR crypts [36] but develop no or very few dMMR adenomas or MSI cancers. Information on incidences of dMMR crypts and dMMR adenomas in path_MSH6 and path_PMS2 carriers is limited. While our previous mathematic modelling was consistent with the linear theory that dMMR crypts initiate the adenoma-carcinoma pathway, it did not indicate that there is necessarily an adenoma stage before an MSI CRC [20]. The findings of the current study indicate that CRCs developing from dMMR crypts may have no or only short sojourn times as adenomas (Figure 4). This is in keeping with a chaotic stochastic pathway initiated by the dMMR/MSI crypts and is similar to ‘the Big Bang’ theory suggested for CRC in the general population [37]. Instead of an accelerated adenoma-carcinoma pathway, our current results may indicate an accelerated stochastic ‘Big Bang’ pathway accounting for most CRCs in path_MSH2, path_MLH1 and path_MSH6 carriers, but not path_PMS2 carriers (Figure 5). A similar theory has been suggested causing cancer in path_BRCA1/2 carriers leading to the same consequences of multiple subclones in one tumour, some of which having no or short sojourn time in adenoma stage [38]. Both these two theories (the one suggesting one Big Bang, the other considering different mutations in different parts of the tumours at different times), are based on recognizing high probabilities for stochastic mutations and may cause the same observed consequences. The theory we propose may explain our previously reported findings of similar or increased incidences of CRC in path_MMR carriers receiving regular colonoscopy compared to historical retrospective cohorts and the lack of any association between time since last colonoscopy and stage of CRC at diagnosis [9, 10, 39] as well as the current finding of no association between incidences of adenomas and CRCs. Noting that more than one mutation may occasionally occur simultaneously in a chaotic stochastic process [37], and that the host immune system may remove invasive cancer cells (as demonstrated by the success of immunotherapy for MSI CRCs in path_MMR carriers), all of our previously reported findings that were in conflict with the accelerated adenoma-carcinoma hypothesis may now be explained. Our current findings and theory are consistent with colonoscopy blocking the adenoma-carcinoma pathway but do not support the accelerated adenoma-carcinoma paradigm as the major cause of increased CRC incidence in path_MMR carriers. Colonoscopy is subject to time-trends. Our results are based on surveillance including colonoscopy that was carried out over several decades in the collaborating centres and they may be considered to represent largely historical observations. More recent and sophisticated colonoscopy techniques may detect smaller adenomas and/or adenomas with different morphological patterns. Staining/chromoendscopy might visualise dMMR crypts and guided or unguided machine learning (artificial intelligence) may provide new ways of interpreting digitalized colonoscopy images [40,41]. The effects of these advances may be a longer mean sojourn time which could increase the probability of colonoscopy preventing CRC. One study using frequent colonoscopies with advanced techniques reported a high incidence of small adenomas and a low incidence of CRC, indicating that improved colonoscopy may reduce CRC incidences [42]. None of this is in conflict with our suggested theory of stochastic processes being the main driver for the CRCs we observed. There are numerous reports on adenomas in the Lynch syndromes but few reports describing the relationships between adenomas and CRCs in carriers subjected to colonoscopy and none that report cumulative incidences of CRC or include sufficient path_MSH6 and path_PMS2 carriers to arrive at meaningful conclusions. Our findings were similar to those in a study of 112 carriers from Cleveland, Ohio among whom CRC was diagnosed only in path_MLH1 and path_MSH2 carriers [43]. A further recent report from Toronto, Ontario on 429 carriers found that more than half of CRCs in path_MMR carriers occurred in patients without adenomas [44]. The methods used did not allow direct comparison with our results. The authors concluded that fewer CRCs were diagnosed in carriers with adenomas when intervals between colonoscopies were shorter, but they did not report findings for short intervals between colonoscopies for the majority of carriers who did not have adenomas. Furthermore, they scored advanced adenomas as CRC and censored observation time when advanced adenomas were found. They did not report cumulative incidences of CRC. The reduced CRC incidence in the minor fraction of carriers who had multiple adenomas and who received more frequent colonoscopy is not in conflict with the minor fraction of carriers with multiple adenomas in our study (Table 2 and Figures 1 and 2) who were too few in number to have an impact on the averages we report or to calculate separate cumulative CRC incidences by age. A study on 136 carriers from Houston, Texas, reported on associations between the presence of adenomas, their stages and CRC [45]. As in the Toronto study, advanced adenomas and CRCs were grouped together and CRC cumulative incidences in carriers with and without adenomas were not reported. Corresponding with our results, they observed no difference in the likelihood of advanced adenomas or CRCs for any of the measured covariates. In North-America there has been a discussion on prophylactic colectomy in path_MMR carriers [46]. But none of the above reports that grouped advanced adenomas and CRC together indicated whether they did so because colectomy was undertaken when advanced adenomas were found, and none is in conflict with our suggested theory of stochastic processes being the main driver for the CRCs we observed. The strengths of our study include the large number of carriers and follow-up years available and that no assumption on the mechanisms underlying CRC was included in the ascertainment criteria. Determination of the results of stochastic processes in time requires sufficient numbers of observations in all strata of interest and sufficient observation time for all strata to reach endpoints. The PLSD was designed to investigate why the observed effects of colonoscopy could not be explained by the accelerated adenoma-carcinoma paradigm alone. Its aim of considering empirical observations in a sufficiently large number of carriers who were subjected to colonoscopy in relation to theories regarding carcinogenetic pathways has been achieved in the current study. CRC incidences in all groups of carriers at all ages have been similar from the first to the most recent PLSD reports, while the numbers of carriers and observation years had tripled, indicating that the CRC incidences in carriers receiving colonoscopy surveillance that are reported by the PLSD are valid. We find no reason to doubt the cumulative incidences of CRCs in carriers with and without adenomas in the current report. The main weakness of our study is that, to our knowledge, it is the only study so far to compare cumulative incidences of adenomas with cumulative incidences of CRCs in all age groups of carriers. Its results have not been validated in an independent replication cohort. We therefore plan to collect data on adenomas from those PLSD contributors who have so far only reported cancers to PLSD. All the information required is likely recorded in medical records but retrieving and contributing these data is requires willingness, ethical approval and funding, resources that may not be available in all contributing centres. The aim of this report was to gain knowledge of adenoma and CRC incidences in path_MMR carriers subjected to regular colonoscopy. We hope the findings may contribute to the refinement of clinical guidelines for the prevention of CRC in path_MMR carriers. Our previous empirical observations and the theories we have suggested to interpret them have been used as arguments for current clinical guidelines [47, 48], but in light of our recent and current findings, some current recommendations may need to be reconsidered. First, since colonoscopy prevents CRC in young path_PMS2 carriers the advice to postpone colonoscopy in young adult path_PMS2 carriers until 35 years of age should be questioned. Second, since undertaking colonoscopy more frequently than every three years may not reduce CRC incidences in path_MLH1 and path_MSH2 carriers, the rationale for more frequent colonoscopies should be questioned. Third, the very minor fraction of path_MMR carriers who have multiple adenomas will be identified at colonoscopy and may be followed more intensively. The driving forces causing their multiple adenomas remain unclear, and empirical knowledge on effects of interventions in this group are limited. Conclusions The PLSD was designed to address why colonoscopy with polypectomy did not reduce CRC incidence as had been assumed by accelerated adenoma-carcinoma model for CRC in path_MMR carriers. Based on combined and concomitant epidemiological and biological findings we propose an alternative model in which there is an accelerated chaotic stochastic pathway to MSI CRC from the dMMR crypt which may cause invasive tumours with no or short sojourn time in adenoma stage. We note, with interest and excitement, that in addition to its applicability in CRC, our model may be relevant to the much wider spectrum of cancers that characterise the four Lynch syndromes. Declarations Ethical Approval Not applicable. Funding PM, EH and MD-V received a grant from The Norwegian Cancer Society, Contract 194751-2017. TTS received grants from Cancer Society Finland, Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, Relander Foundation and the Academy of Finland. DGE is funded by the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007), IS-BRC-1215-20007. Availability of data and materials The tables are the raw data grouped as indicated. Figure 1 is based on Table 2. The complete SQL code for how the grouped data underlying Figure 3 was extracted from the MySQL database is published in reference #22. Anonymized data underlying Figure 2, the annual incidences by age group underlying figure 3 are available upon request, both pending written agreement that none of these will be used for any other purpose than confirming the figures to be correct. Authors' contributions PM designed the study, calculated the results and drafted the paper. PM, SH, AA, MK, JRS and LS together developed the suggested model for carcinogenesis. All authors substantially contributed to the conception and design of the final manuscript and/or revised it for intellectual content and approved it. Acknowledgments EHTG is a charitable company registration number SC048407 in Scotland. EHTG is the legal host for PLSD. Anyone may contribute to and become part of the PLSD – for details see www.ehtg.org . Informed consent for publishing data Not applicable Competing interests Toni T. Seppälä: Healthfund Finland (CEO and stock holding), LS Cancer Diag (advisory board and stock holding) and Amgen Finland (speaker honorarium). References Møller P, Seppälä TT, Ahadova A, et al. Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement. Hered Cancer Clin Pract. 2023 Oct 11;21(1):19. doi: 10.1186/s13053-023-00263-3. PMID: 37821984; PMCID: PMC10568908. https://pubmed.ncbi.nlm.nih.gov/37821984/ https://www.omim.org/ Accessed April 2 nd 2024 Chan TA, Wang Z, Dang LH, Vogelstein B, Kinzler KW. Targeted inactivation of CTNNB1 reveals unexpected effects of beta-catenin mutation. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8265-70. doi: 10.1073/pnas.082240999. 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Clin Gastroenterol Hepatol. 2023 Mar;21(3):581-603.e33. doi: 10.1016/j.cgh.2022.12.006. Epub 2022 Dec 20. PMID: 36549470. https://pubmed.ncbi.nlm.nih.gov/36549470/ Seppälä TT, Latchford A, Negoi I, et al. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. Br J Surg. 2021 May 27;108(5):484-498. doi: 10.1002/bjs.11902. PMID: 34043773; PMCID: PMC10364896. https://pubmed.ncbi.nlm.nih.gov/34043773/ Tables Table 1 Number of carriers by sex and gene, average age and number of adenomas with 95% CI, number of adenomas by grade, and total number of adenomas. Gene Sex Number Follow-up years (mean) Mean age (95% CI) Number of adenomas Total Mean (95% CI) Advanced Path_MSH2 M 574 6,206 (10.8) 53.0 (1.2) 554 0.97 (0.16) 66 F 661 6,689 (10.1) 53.6 (1.2) 519 0.79 (0.15) 59 Path_MLH1 M 649 8,880 (13.7) 54.4 (1.1) 519 0.80 (0.13) 50 F 719 10,126 (14.1) 56.0 (1.1) 544 0.76 (0.15) 52 Path_MSH6 M 346 2,680 (7.7) 57.0 (1.7) 311 0.90 (0.21) 33 F 426 3,123 (7.3) 56.2 (1.6) 243 0.57 (0.15) 12 Path_PMS2 M 85 415 (4.9) 56.0 (3.4) 39 0.46 (0.22) 0 F 114 616 (5.4) 52.8 (2.7) 38 0.33 (0.18) 4 Sum 3,574 38,735 2,767 276 Table 2 Number of carriers by gene and sum adenomas, also indicating numbers of adenomas, unclassified polyps, hyperplastic, serrated, juvenile, hamartomas, total number of polyps and average age in group. Gene N Number adenomas in each carrier in group (row) Number of carriers within group (row) with other polyps, by polyp type unclassified hyperplastic serrated juvenile hamartomas Mean age Path_MLH1 907 0 0 0 0 0 0 53.6 227 1 0 2 0 0 0 54.8 105 2 0 0 0 0 0 60.8 61 3 0 0 0 0 0 63.3 28 4 0 2 0 0 0 59.8 12 5 1 0 0 0 0 61.3 9 6 1 0 0 0 0 67.4 6 7 1 0 0 0 0 71.5 6 8 4 0 0 0 0 66.7 1 9 0 0 0 0 0 40.0 1 11 0 0 0 0 0 54.0 2 15 2 0 0 0 0 64.5 1 18 0 0 2 0 0 57.0 1 20 0 0 2 0 0 72.0 1 39 0 0 12 0 0 79.0 Path_MSH2 812 0 0 0 0 0 0 50.8 194 1 0 0 0 0 0 55.7 105 2 0 0 0 0 0 57.1 40 3 0 0 0 0 0 63.3 32 4 0 5 0 0 0 59.3 10 5 0 0 0 0 0 68.2 12 6 0 0 0 0 0 65.7 4 7 0 0 0 0 0 65.8 11 8 0 6 2 0 0 64.8 3 9 0 0 1 0 0 66.3 3 10 0 2 0 0 0 60.0 3 11 0 3 0 0 0 57.7 2 12 0 4 9 0 0 50.0 3 13 0 0 0 0 0 63.7 1 30 0 4 0 0 0 80.0 Path_MSH6 567 0 0 0 0 0 0 53.6 77 1 0 0 0 0 0 62.7 56 2 0 2 0 0 0 65.0 33 3 0 0 0 0 0 64.7 12 4 0 4 0 0 0 72.1 5 5 0 0 1 0 0 62.4 9 6 0 6 0 0 0 64.3 1 7 0 0 0 0 0 45.0 3 8 0 4 0 0 0 82.7 2 9 0 2 1 0 0 74.0 2 10 2 0 0 0 0 59.5 1 11 0 0 0 0 0 67.0 1 12 0 1 0 0 0 80.0 1 15 0 0 0 0 0 79.0 2 16 0 4 0 0 0 62.5 Path_ PMS2 158 0 0 0 0 0 0 52.7 23 1 0 2 1 0 0 57.5 10 2 0 0 0 0 0 62.3 3 3 0 0 0 0 0 58.0 3 4 0 0 0 0 0 69.0 1 5 0 4 0 0 0 56.0 1 8 0 0 0 0 0 72.0 Table 3 Numbers, follow-up years and prospectively detected CRCs in carriers with and without adenomas in last colonoscopy before CRC; and without CRC before or at first colonoscopy (prevalence round), by genetic variants. Gene Number carriers Follow-up years Number CRC Carriers with adenoma(s) Path_MLH1 554 7,567 82 Path_MSH2 518 5,125 47 Path_MSH6 402 2,775 10 Path_PMS2 116 538 0 Sum 1,590 16,005 Carriers without adenoma Path_MLH1 329 5,778 69 Path_MSH2 231 3,068 28 Path_MSH6 114 1,134 3 Path_PMS2 29 228 0 Sum 703 10,208 Total 2,293 26,213 239 Table 4 Number having no polyps, adenomas or other polyps (not classified or otherwise classified) detected at last colonoscopy before CRC diagnosed by gene, age at CRC diagnosed, and months since last colonoscopy before CRC was diagnosed. Gene adenoma N Mean months before (95% CI) Mean age (95% CI) Path_MLH1 No 83 26.7 (2.8) 53.1 (2.8) Yes 35 29.4 (8.5) 52.7 (3.7) Path_MSH2 No 59 35.1 (8.9) 52.6 (3.0) Yes 25 27.9 (9.7) 54.0 (4.5) Path_MSH6 No 8 20.6 (7.7) 58.8 (7.5) Yes 5 28.6 (14.6) 52.0 (15.1) Additional Declarations No competing interests reported. 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Charlotte","middleName":"","lastName":"Lautrup","suffix":""},{"id":290776963,"identity":"54fa8922-3ba4-45b1-b9e2-55dc6bdd08b4","order_by":24,"name":"Louvise L Klarskov","email":"","orcid":"","institution":"29.\tDept of Pathology, Copenhagen University Hospital - Herlev and Gentofte","correspondingAuthor":false,"prefix":"","firstName":"Louvise","middleName":"L","lastName":"Klarskov","suffix":""},{"id":290776964,"identity":"1170cb65-9bfe-4a7e-b785-4ebd00c8b40d","order_by":25,"name":"Giulia Martina Cavestro","email":"","orcid":"","institution":"31.\tGastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"Martina","lastName":"Cavestro","suffix":""},{"id":290776966,"identity":"7113ff9c-f42d-4d75-9d5a-a7d1788f807c","order_by":26,"name":"Gabriela Möslein","email":"","orcid":"","institution":"32.\tSurgical Center for Hereditary Tumors, Ev. Bethesda Khs Duisburg, University Düsseldorf","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"","lastName":"Möslein","suffix":""},{"id":290776967,"identity":"28373c60-ae3e-4b80-b990-e67450d38b09","order_by":27,"name":"Eivind Hovig","email":"","orcid":"","institution":"1.\tDepartment of Tumour Biology, Institute of Cancer Research, The Norwegian Radium Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eivind","middleName":"","lastName":"Hovig","suffix":""},{"id":290776968,"identity":"119d159a-e4b0-45f6-99a9-2367f16ef00c","order_by":28,"name":"Mev Dominguez-Valentin","email":"","orcid":"","institution":"1.\tDepartment of Tumour Biology, Institute of Cancer Research, The Norwegian Radium Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mev","middleName":"","lastName":"Dominguez-Valentin","suffix":""}],"badges":[],"createdAt":"2024-04-08 20:29:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4238470/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4238470/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54694240,"identity":"6ec76601-9bfa-4dde-835a-183f5cc3e17a","added_by":"auto","created_at":"2024-04-15 10:49:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73261,"visible":true,"origin":"","legend":"\u003cp\u003ePie-charts showing total number of colorectal adenomas by genetic variant\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-4238470/v1/bb8238c73b38ab5d19a030e7.png"},{"id":54694239,"identity":"3ed39f30-f83b-42b2-9d2c-fd774fcac611","added_by":"auto","created_at":"2024-04-15 10:49:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":139597,"visible":true,"origin":"","legend":"\u003cp\u003eStandard linear regression on the total number of colorectal adenomas by genetic variant and age for age up to 80 years at last examination. \u003cem\u003ePath_PMS2 \u003c/em\u003ecarriers had less than the others (p\u0026lt;0.01). Only a few at any age and with any genetic variant had multiple colorectal adenomas. Regression line for MLH1 is hidden under MSH6.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-4238470/v1/811f0c903918d8c7b56210b4.png"},{"id":54694243,"identity":"a91f2acf-3aa4-45a8-9e07-7ca6184c59c4","added_by":"auto","created_at":"2024-04-15 10:49:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":65846,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidences of CRC in \u003cem\u003epath_MLH1, path MSH2 \u003c/em\u003eand \u003cem\u003epath_MSH6\u003c/em\u003e carriers with and without colorectal adenoma(s).\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-4238470/v1/a1fc15c0491f08b2718e59d6.png"},{"id":54694241,"identity":"569c92f7-3802-43af-be16-a60c745fb6a2","added_by":"auto","created_at":"2024-04-15 10:49:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1296661,"visible":true,"origin":"","legend":"\u003cp\u003ePossible pathways to CRC in LS modified from [6]. Carcinogenesis in LS follows a stochastic process where two major selection pressures apply: selection through conferred growth advantage and counter-selection through the immune system. MMR-deficient crypts may undergo immune elimination (arrows at the bottom central part of the graphic pointing to an empty space left by the eliminated crypt and now filled with immune cells), and MMR-deficient adenomas and cancers might be eliminated by the immune system, too (not shown by arrows). However, cancer may still arise via at least three pathways depicted here. Cancers arising through Pathway 1 may have a longer sojourn time as adenomas, as they spend part of their progression as MMR-proficient adenomas and only later acquire MMR deficiency. At this stage, Pathway 1-cancers can be prevented by colonoscopy. If not prevented, further mutations could accumulate eventually leading to cancer. Cancers arising through Pathway 2 may have shorter sojourn time as adenomas compared to Pathway 1, as they develop from initially MMR-deficient crypts acquiring further mutations to develop into MMR-deficient adenomas, thus not spending time as MMR-proficient lesions. However, the sojourn time as adenoma in Pathway 2 is longer compared to cancers arising through Pathway 3. The latter cancers likely have no sojourn time as adenomas and arise upon a single somatic hit (cnLOH) activating beta-catenin and inactivating MLH1. According to the current knowledge, this pathway is therefore specific for MLH1 carriers. Red arrows indicate regression due to counterselection by the immune system, black arrows indicate progression due to gained growth advantage, dotted black arrows indicate hypothetical progression if removal by colonoscopy did not take place.\u003c/p\u003e\n\u003cp\u003eAttribution: Hourglass element is an image by freepik.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-4238470/v1/3eb8a29ce0f3aaea281075e8.png"},{"id":54694242,"identity":"7cd7fbff-f283-4ccc-9cbc-18087701a13d","added_by":"auto","created_at":"2024-04-15 10:49:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":39043,"visible":true,"origin":"","legend":"\u003cp\u003eSimplified diagram of possible pathways to MSI CRC in \u003cem\u003epath_MMR \u003c/em\u003ecarriers, modified from [6, 20], compliant with Figure 4 and specifying the accelerated chaotic stochastic process Big Bang theory [37] as discussed in the text.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAPC\u003c/em\u003e inactivation occurs prior to loss of the wild-type MMR allele resulting in adenoma initiation. Subsequent loss of the second MMR allele in the adenoma generates a dMMR clone with increased risk of progression to cancer.\u003c/p\u003e\n\u003cp\u003eThe initial event is loss of the second MMR allele resulting in a dMMR crypt causing an accelerated stochastic chaotic probability of mutations (that is greater for \u003cem\u003epath_MLH1\u003c/em\u003e and\u003cem\u003e path_MSH2 \u003c/em\u003ecompared to\u003cem\u003e path_MSH6 \u003c/em\u003eand only marginally raised in \u003cem\u003ePath_PMS2\u003c/em\u003e). Many different driver genes may be mutated and in different orders [38], causing no or only a short sojourn time of tumours as adenomas. A dMMR cell may also become a dMMR adenoma.\u003c/p\u003e\n\u003cp\u003eIn \u003cem\u003epath_MLH1\u003c/em\u003e carriers, a single LOH event at chromosome 3p22 may inactivate the wild-type alleles of the co-located \u003cem\u003eCTNNB1\u003c/em\u003e and \u003cem\u003eMLH1 \u003c/em\u003egenes (in a cell that has already sustained a single \u003cem\u003eCTNNB1\u003c/em\u003e mutation, usually at codon 41 or 45 in Exon3). This specific initiating event may occur in up to 40% of CRC in Path_MLH1 carriers [32].\u003c/p\u003e\n\u003cp\u003eRegular colonoscopy may block the adenoma-carcinoma pathway. dMMR/MSI crypts, adenomas and cancer might be removed by the host immune system. Mutated genes in black. pMMR adenoma: MMR proficient adenoma. dMMR adenoma: MMR deficient adenoma.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-4238470/v1/35c667568646ca6ad8c2108f.png"},{"id":54694708,"identity":"a01839b1-795a-4587-8f92-40cb1fd223a2","added_by":"auto","created_at":"2024-04-15 10:57:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1507954,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4238470/v1/5c6a4069-7dd3-4639-be97-cace450cbaf3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes","fulltext":[{"header":"Background","content":"\u003cp\u003eThere are four dominantly inherited microsatellite instability (MSI) Lynch syndromes, caused by pathogenic variants of the four \u003cem\u003eMMR (path_MMR)\u003c/em\u003e genes\u003cem\u003e\u0026nbsp;MLH1, MSH2, MSH6 and PMS2\u003c/em\u003e (OMIM \u003cstrong\u003e#\u003c/strong\u003e 120435; \u003cstrong\u003e#\u003c/strong\u003e 609310; #614350 and #614337) [1, 2]. Deletions of the \u003cem\u003eEPCAM\u003c/em\u003e tail #613244 epigenetically silence the \u003cem\u003eMSH2\u003c/em\u003e gene and in this report are grouped together with OMIM \u003cstrong\u003e#\u003c/strong\u003e 120435. The four \u003cem\u003epath_MMR\u003c/em\u003e variant groups have different penetrance (incidence of any cancer) and expressivities (incidences of cancer in the different affected organs), causing different overall risks of death related to any cancer and to cancer in specific organs [1]. CRC in the normal population is assumed to most often arise through biallelic somatic \u003cem\u003eAPC\u003c/em\u003e mutations initiating an adenoma that may develop into a CRC as a result of acquiring additional driver mutations, and less often through an initiating \u003cem\u003eCTNNB1\u003c/em\u003e mutation [3, 4]. Assuming that CRCs in \u003cem\u003epath_MMR\u003c/em\u003e carriers develop from adenomas, and observing that carriers do not have many adenomas, the paradigm of an accelerated adenoma-carcinoma pathway was established in the Lynch syndromes [5]. The mechanism for the accelerated pathway was assumed to be mediated via deficiency of MMR proteins (dMMR) in MSI adenomas [6]. It soon became clear that colonoscopy with polypectomy (below referred to as colonoscopy) every third year did not prevent CRC in carriers as had been hoped and more frequent colonoscopies were advocated [7]. However, large studies reported that shorter intervals between colonoscopies reduced neither CRC incidences in \u003cem\u003epath_MMR\u003c/em\u003e carriers nor its stage at diagnosis [8, 9]. To assess the incidence and prognosis of CRC in path_MMR carriers subjected to colonoscopy as is advocated in clinical guidance, the European Hereditary Tumour Group (EHTG, www.ehtg.org, at that time named The Mallorca Group) initiated the Prospective Lynch Syndrome Database (PLSD, www.plsd.eu ). When comparing CRC incidences in carriers followed up in PLSD who were subjected to colonoscopy surveillance with other cohorts of carriers who did not all receive colonoscopy surveillance, the CRC incidences in \u003cem\u003epath_MLH1, path_MSH2\u003c/em\u003e and \u003cem\u003epath_MSH6\u003c/em\u003e carriers were either increased or not reduced in PLSD, depending on which retrospective segregation analyses were used in the comparator groups [10\u0026ndash;13]. By contrast, CRC incidences in path_PMS2 carriers followed up in PLSD were reduced [14]. A recent position statement by the EHTG discusses that these findings may be in keeping with emerging knowledge that adult \u003cem\u003epath_MLH1\u003c/em\u003e and \u003cem\u003epath_MSH2\u003c/em\u003e carriers have huge numbers of MMR-deficient crypts (dMMR) arising in their colons [15-17]. It appears that these may be controlled or destroyed by the immune system or may develop into CRC without an intermediate adenoma stage. Further, it is now also clear that not only dMMR crypts, but also dMMR/MSI CRCs may be removed by the host immune system, as demonstrated by the success of immune checkpoint blockade therapy [1, 18, 19].\u003c/p\u003e\n\u003cp\u003ePrevious studies using the PLSD have provided new data and insights into the associations between colonoscopy intervals, incidences of CRC by age and times from a normal surveillance colonoscopy to diagnosis of CRC, its stage at diagnosis and prognosis. In this report we add new data on the incidences of colorectal adenomas and their relationship to the incidences of CRC.\u003c/p\u003e\n\u003cp\u003eAims\u003c/p\u003e\n\u003cp\u003eThe aims were to determine the incidences of colorectal adenomas by age and gene in \u003cem\u003epath_MMR\u003c/em\u003e carriers, compare these with the incidences of CRC and evaluate the results in relation to previously reported paradigms [5, 3] and our previously suggested hypotheses regarding pathways to CRC in the Lynch syndromes [1, 6, 20] thereby better informing future clinical guidelines for prevention and treatment.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe PLSD was initiated in 2012 and the first report on CRC incidences, stratified by \u003cem\u003eMMR\u003c/em\u003e gene was published in 2015 [21]. Since then, the number of individuals under follow up in PLSD has tripled, while the incidences of CRC by age, gene and gender have remained similar, leading us to conclude that the incidences have been validated in the newly recruited cases. The methods used and our most recent results have been described in detail [1,22-24] (www.plsd.eu). In the current study, as detailed in our previous reports, cumulative incidences of CRC were calculated from 25 to 75 years of age as time to first CRC in carriers who had not had CRC prior to or at their first prospectively planned and completed colonoscopy. Overall 10 year survival following CRC was estimated.\u003c/p\u003e\n\u003cp\u003ePolyps were grouped as adenomas or non-adenomatous polyps, and adenomas were grouped as either advanced or not (advanced adenomas = those \u0026gt;10mm diameter and/or villous morphology and/or high grade dysplasia). The total number of adenomas removed up to and including at the last colonoscopy was noted for each \u003cem\u003epath_MMR\u003c/em\u003e carrier. We compared incidences of adenomas by age and gene using standard linear regression analysis. We also report on the presence or absence of adenomas at the last colonoscopy undertaken before CRC was diagnosed and the time between that last colonoscopy and the diagnosis of CRC. Carriers were grouped into those who had ever had adenoma(s) and those who had not and cumulative incidences of CRC were compared, stratified by age and by gene.\u003c/p\u003e\n\u003cp\u003eWe discuss the results using the concept of mean sojourn time which makes no assumptions regarding mechanisms for what is observed [25], as is usual when examining the effectiveness of screening in cancer prevention. This may be explained as follows: \u0026lsquo;\u003cem\u003eThe parameter estimated in practice in screening programs is the average sojourn time over all disease cases, usually referred to as the mean sojourn time. A long mean sojourn time indicates a good potential for screening. The shorter the sojourn time, the more frequently screening has to take place in order to be effective. If the mean sojourn time is very short, screening may not be worthwhile at all\u003c/em\u003e.\u0026rsquo; [26]. Screening colonoscopy to prevent CRC is based on the adenoma-carcinoma paradigm [5] with detection and removal of tumours at the adenoma stage. Here we consider sojourn time as the time for which the tumour is detectable as an adenoma by colonoscopy. PLSD records discrete observations in time that are assumed to be Poisson-distributed [27] and that may be considered based on the paradigm of stochastic causative processes [28, 29]\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe required details were available for 3,574 carriers who were followed for 38,735 years after their initial (prevalence) colonoscopies. The mean ages of male and female carriers in each path_MMR group were similar at the end of the study (range 52.8 to 57.0 years, see details in Table 1). 2,444 (68%) had never had a colorectal adenoma detected at colonoscopy and 1,130 (32%) had one or more colorectal adenomas detected, all of which were removed.\u003c/p\u003e\n\u003cp\u003eThe detailed findings, grouping carriers by gene, their total number of adenomas (advanced and not advanced) and the numbers of non-adenomatous polyps (categorised as unclassified, hyperplastic, serrated, juvenile or hamartomatous), total number of polyps and average age in each group are given in Table 2. The numbers in Table 2 are illustrated as pie-charts of the number of adenomas in carriers by gene in Figure 1, and as results of standard linear regression of the number of adenomas by carrier and by gene in Figure 2.\u003c/p\u003e\n\u003cp\u003eAnnual incidences of both CRC and colorectal adenomas increased with age (Table 2 and Figure 3) as previously reported by others [30].\u003c/p\u003e\n\u003cp\u003eThere was no statistically significant difference in the prevalence of adenomas in \u003cem\u003epath_MLH1\u003c/em\u003e versus \u003cem\u003epath_MSH2\u003c/em\u003e carriers but both \u003cem\u003epath_MSH6\u003c/em\u003e and \u003cem\u003epath_ PMS2\u003c/em\u003e carriers were significantly less likely to have any adenomas than were \u003cem\u003epath_MLH1\u003c/em\u003e or \u003cem\u003epath_MSH2\u003c/em\u003e carriers (p\u0026lt;0.001). In contrast, among carriers with adenomas \u003cem\u003epath_MLH1\u003c/em\u003e, \u003cem\u003epath_MSH2\u003c/em\u003e and \u003cem\u003epath_MSH6\u003c/em\u003e carriers all had similar regression curves for numbers of adenomas, while \u003cem\u003epath_PMS2\u003c/em\u003e carriers less frequently had multiple adenomas (Figure 2 and Figure 3, p\u0026lt;0.01). Advanced adenomas were with one exception seen only in carriers with multiple adenomas. Serrated adenomas were rarely seen (Table 2). If, as we propose, adenomas may disappear spontaneously in \u003cem\u003epath_MMR\u003c/em\u003e carriers because of targeting by the host immune system, the cumulative incidences of adenomas shown in Figure 3 may be underestimates.\u003c/p\u003e\n\u003cp\u003eAs seen in Table 2, 34%, 34%, 27% and 21% of \u003cem\u003epath_MLH1\u003c/em\u003e, \u003cem\u003epath_MSH2, path_MSH6\u003c/em\u003e and \u003cem\u003epath_PMS2\u003c/em\u003e carriers had one or more adenomas and only 5%, 7%, 5% and 4%, respectively, had more than 3 adenomas. There were therefore insufficient numbers to calculate meaningful cumulative incidences of CRC by age in carriers with multiple adenomas.\u003c/p\u003e\n\u003cp\u003eAmong the 3,574 carriers included in the study, 2,293 (64%) had no CRC before or at the first planned and carried out (prevalence round) colonoscopy. They were followed-up with regular colonoscopy for 26,213 years and 239 CRCs were diagnosed prospectively in carriers from 25 to 75 years of age. Details are given in Table 3. These included 151, 85, 12 and 1 CRCs in carriers of \u003cem\u003epath_MLH1, path_MSH2, path_MSH6\u0026nbsp;\u003c/em\u003eand\u003cem\u003e\u0026nbsp;path_PMS2\u003c/em\u003e, respectively.\u003c/p\u003e\n\u003cp\u003eTable 4 shows the numbers of carriers with and without adenomas at the last colonoscopy before diagnosis of CRC, together with the number of months elapsed between the last colonoscopy and diagnosis of CRC. In each group of \u003cem\u003epath_MMR\u003c/em\u003e carriers, the majority had no adenomas at the last colonoscopy and the months elapsed were similar in carriers with and without adenomas.\u003c/p\u003e\n\u003cp\u003eAs seen in Figure 3, there were no differences in the cumulative incidences of CRC by gene in \u003cem\u003epath_MLH1, path_MSH2\u0026nbsp;\u003c/em\u003eand\u003cem\u003e\u0026nbsp;path_MSH6\u0026nbsp;\u003c/em\u003ecarriers stratified by the presence or absence of adenomas (the curves are overlapping and no confidence estimates or calculation of p-values were needed to reach this conclusion).\u003c/p\u003e\n\u003cp\u003eNo CRC was diagnosed prospectively in \u003cem\u003epath_PMS2\u003c/em\u003e carriers below 75 years of age.\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in 10-year overall survival after first prospectively detected CRC in carriers with and without adenomas (88% and 81%, p\u0026gt;0.05 respectively).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this study are that 1) the majority of \u003cem\u003epath_MMR\u003c/em\u003e carriers did not develop any colorectal adenoma(s) during follow up, 2) colonoscopy appeared to prevent CRC in path_PMS2 carriers but not in the others, and 3) there was no association between the incidences of adenomas and CRCs in any group of carriers.\u003c/p\u003e\n\u003cp\u003eIn contrast to previous reports on carriers not subjected to colonoscopy [14], no CRC was diagnosed prospectively in \u003cem\u003epath_PMS2\u003c/em\u003e carriers below 75 years of age, to the combined conclusion that colonoscopy as undertaken had prevented CRC in \u003cem\u003epath_PMS2\u003c/em\u003e carriers in the current study.\u003c/p\u003e\n\u003cp\u003eThe lower incidences of colorectal adenomas in path_PMS2 carriers compared to \u003cem\u003epath_MLH1, path_MSH2 \u003c/em\u003eand\u003cem\u003e path_MSH6\u003c/em\u003e carriers, may suggest that some adenomas in the latter groups are attributable to the \u003cem\u003epath_MMR\u003c/em\u003e genotypes.\u003c/p\u003e\n\u003cp\u003eConsidered in relation to the sojourn time paradigm, the PLSD findings are in keeping with a theory that colonoscopy blocks the adenoma-carcinoma pathway and that the CRCs observed had no or short sojourn times as adenomas. CRCs arising by the CTNNB1 pathway appear to have no sojourn time as adenomas [3], are not frequent in \u003cem\u003epath_MMR\u003c/em\u003e carriers [31], and may be specific for \u003cem\u003epath_MMR\u003c/em\u003e carriers [32-34].\u003c/p\u003e\n\u003cp\u003eOur findings pose the following question: if the adenoma-carcinoma pathway that is initiated by APC mutation [3, 6, 31] is blocked by colonoscopy and the carcinogenetic pathway has to include an early mutation causing an increased cell proliferation rate [3, 20], how have the observed CRCs emerged? There are many published pathophysiological, biochemical and DNA analyses of adenomas and CRCs. Based on these, we have suggested an additional pathway in \u003cem\u003epath_MMR\u003c/em\u003e carriers in which dMMR crypts may trigger the adenoma-carcinoma pathway [6]. A recent mathematical analysis of the most frequently mutated genes in CRCs supported this theory [20].\u003c/p\u003e\n\u003cp\u003eDescriptions of tumours reflect different time-points in different carcinogenetic processes and, when tumours are removed for observation, subsequent events that might have occurred are blocked (\u0026ldquo;\u003cem\u003ethe very act of measurement or observation directly alters the phenomenon under investigation\u0026rdquo;)\u003c/em\u003e [35]. In relation to the adenoma-carcinoma sequence, there would be obvious ethical problems with any study proposing to observe the transition of adenomas to CRCs in humans and, in addition, there is no way of fully characterising an adenoma or CRC without altering it. As no direct observations of the order of events in carcinogenetic processes are possible, the suggested linear models that are based on biological findings in adenomas and CRCs are assumed, not observed. In addition, mutations observed in adenomas and CRCs are influenced by selection (in \u003cem\u003epath_MMR\u003c/em\u003e carriers including survival in the face of the host immune system\u0026rsquo;s continuous efforts to identify and remove the tumours) and genetic drift which may involve interacting stochastic processes. \u003c/p\u003e\n\u003cp\u003eWhen re-examining the arguments for our previous suggestion of three linear pathways to CRC in \u003cem\u003epath_MMR\u003c/em\u003e carriers [6] and adding the findings reported in this paper, we conclude that the following model is probable: The main pathway to CRC in \u003cem\u003epath_MMR\u003c/em\u003e carriers may be triggered by a second-hit in the wild-type MMR allele leading to a dMMR crypt and increasing the acquisition of mutations in driver genes [3, 20] in a continuous chaotic stochastic process which may lead to CRC. The probability of any one dMMR clone leading to CRC seems to be very low. Adult \u003cem\u003epath_MLH1\u003c/em\u003e and \u003cem\u003epath_MSH2\u003c/em\u003e carriers have thousands of dMMR crypts [36] but develop no or very few dMMR adenomas or MSI cancers. Information on incidences of dMMR crypts and dMMR adenomas in \u003cem\u003epath_MSH6\u003c/em\u003e and \u003cem\u003epath_PMS2\u003c/em\u003e carriers is limited. While our previous mathematic modelling was consistent with the linear theory that dMMR crypts initiate the adenoma-carcinoma pathway, it did not indicate that there is necessarily an adenoma stage before an MSI CRC [20]. \u003c/p\u003e\n\u003cp\u003eThe findings of the current study indicate that CRCs developing from dMMR crypts may have no or only short sojourn times as adenomas (Figure 4). This is in keeping with a chaotic stochastic pathway initiated by the dMMR/MSI crypts and is similar to \u0026lsquo;the Big Bang\u0026rsquo; theory suggested for CRC in the general population [37]. Instead of an accelerated adenoma-carcinoma pathway, our current results may indicate an accelerated stochastic \u0026lsquo;Big Bang\u0026rsquo; pathway accounting for most CRCs in \u003cem\u003epath_MSH2, path_MLH1 \u003c/em\u003eand \u003cem\u003epath_MSH6 \u003c/em\u003ecarriers, but not\u003cem\u003e path_PMS2\u003c/em\u003e carriers (Figure 5). A similar theory has been suggested causing cancer in \u003cem\u003epath_BRCA1/2\u003c/em\u003e carriers leading to the same consequences of multiple subclones in one tumour, some of which having no or short sojourn time in adenoma stage [38]. Both these two theories (the one suggesting one Big Bang, the other considering different mutations in different parts of the tumours at different times), are based on recognizing high probabilities for stochastic mutations and may cause the same observed consequences.\u003c/p\u003e\n\u003cp\u003eThe theory we propose may explain our previously reported findings of similar or increased incidences of CRC in \u003cem\u003epath_MMR\u003c/em\u003e carriers receiving regular colonoscopy compared to historical retrospective cohorts and the lack of any association between time since last colonoscopy and stage of CRC at diagnosis [9, 10, 39] as well as the current finding of no association between incidences of adenomas and CRCs. Noting that more than one mutation may occasionally occur simultaneously in a chaotic stochastic process [37], and that the host immune system may remove invasive cancer cells (as demonstrated by the success of immunotherapy for MSI CRCs in \u003cem\u003epath_MMR\u003c/em\u003e carriers), all of our previously reported findings that were in conflict with the accelerated adenoma-carcinoma hypothesis may now be explained. Our current findings and theory are consistent with colonoscopy blocking the adenoma-carcinoma pathway but do not support the accelerated adenoma-carcinoma paradigm as the major cause of increased CRC incidence in \u003cem\u003epath_MMR\u003c/em\u003e carriers.\u003c/p\u003e\n\u003cp\u003eColonoscopy is subject to time-trends. Our results are based on surveillance including colonoscopy that was carried out over several decades in the collaborating centres and they may be considered to represent largely historical observations. More recent and sophisticated colonoscopy techniques may detect smaller adenomas and/or adenomas with different morphological patterns. Staining/chromoendscopy might visualise dMMR crypts and guided or unguided machine learning (artificial intelligence) may provide new ways of interpreting digitalized colonoscopy images [40,41]. The effects of these advances may be a longer mean sojourn time which could increase the probability of colonoscopy preventing CRC. One study using frequent colonoscopies with advanced techniques reported a high incidence of small adenomas and a low incidence of CRC, indicating that improved colonoscopy may reduce CRC incidences [42]. None of this is in conflict with our suggested theory of stochastic processes being the main driver for the CRCs we observed.\u003c/p\u003e\n\u003cp\u003eThere are numerous reports on adenomas in the Lynch syndromes but few reports describing the relationships between adenomas and CRCs in carriers subjected to colonoscopy and none that report cumulative incidences of CRC or include sufficient \u003cem\u003epath_MSH6\u003c/em\u003e and\u003cem\u003e path_PMS2\u003c/em\u003e carriers to arrive at meaningful conclusions. Our findings were similar to those in a study of 112 carriers from Cleveland, Ohio among whom CRC was diagnosed only in \u003cem\u003epath_MLH1\u003c/em\u003e and \u003cem\u003epath_MSH2\u003c/em\u003e carriers [43]. A further recent report from Toronto, Ontario on 429 carriers found that more than half of CRCs in \u003cem\u003epath_MMR\u003c/em\u003e carriers occurred in patients without adenomas [44]. The methods used did not allow direct comparison with our results. The authors concluded that fewer CRCs were diagnosed in carriers with adenomas when intervals between colonoscopies were shorter, but they did not report findings for short intervals between colonoscopies for the majority of carriers who did not have adenomas. Furthermore, they scored advanced adenomas as CRC and censored observation time when advanced adenomas were found. They did not report cumulative incidences of CRC. The reduced CRC incidence in the minor fraction of carriers who had multiple adenomas and who received more frequent colonoscopy is not in conflict with the minor fraction of carriers with multiple adenomas in our study (Table 2 and Figures 1 and 2) who were too few in number to have an impact on the averages we report or to calculate separate cumulative CRC incidences by age.\u003c/p\u003e\n\u003cp\u003eA study on 136 carriers from Houston, Texas, reported on associations between the presence of adenomas, their stages and CRC [45]. As in the Toronto study, advanced adenomas and CRCs were grouped together and CRC cumulative incidences in carriers with and without adenomas were not reported. Corresponding with our results, they observed no difference in the likelihood of advanced adenomas or CRCs for any of the measured covariates.\u003c/p\u003e\n\u003cp\u003eIn North-America there has been a discussion on prophylactic colectomy in \u003cem\u003epath_MMR\u003c/em\u003e carriers [46]. But none of the above reports that grouped advanced adenomas and CRC together indicated whether they did so because colectomy was undertaken when advanced adenomas were found, and none is in conflict with our suggested theory of stochastic processes being the main driver for the CRCs we observed.\u003c/p\u003e\n\u003cp\u003eThe strengths of our study include the large number of carriers and follow-up years available and that no assumption on the mechanisms underlying CRC was included in the ascertainment criteria. Determination of the results of stochastic processes in time requires sufficient numbers of observations in all strata of interest and sufficient observation time for all strata to reach endpoints. The PLSD was designed to investigate why the observed effects of colonoscopy could not be explained by the accelerated adenoma-carcinoma paradigm alone. Its aim of considering empirical observations in a sufficiently large number of carriers who were subjected to colonoscopy in relation to theories regarding carcinogenetic pathways has been achieved in the current study. CRC incidences in all groups of carriers at all ages have been similar from the first to the most recent PLSD reports, while the numbers of carriers and observation years had tripled, indicating that the CRC incidences in carriers receiving colonoscopy surveillance that are reported by the PLSD are valid. We find no reason to doubt the cumulative incidences of CRCs in carriers with and without adenomas in the current report.\u003c/p\u003e\n\u003cp\u003eThe main weakness of our study is that, to our knowledge, it is the only study so far to compare cumulative incidences of adenomas with cumulative incidences of CRCs in all age groups of carriers. Its results have not been validated in an independent replication cohort. We therefore plan to collect data on adenomas from those PLSD contributors who have so far only reported cancers to PLSD. All the information required is likely recorded in medical records but retrieving and contributing these data is requires willingness, ethical approval and funding, resources that may not be available in all contributing centres.\u003c/p\u003e\n\u003cp\u003eThe aim of this report was to gain knowledge of adenoma and CRC incidences in path_MMR carriers subjected to regular colonoscopy. We hope the findings may contribute to the refinement of clinical guidelines for the prevention of CRC in \u003cem\u003epath_MMR\u003c/em\u003e carriers. Our previous empirical observations and the theories we have suggested to interpret them have been used as arguments for current clinical guidelines [47, 48], but in light of our recent and current findings, some current recommendations may need to be reconsidered. First, since colonoscopy prevents CRC in young \u003cem\u003epath_PMS2\u003c/em\u003e carriers the advice to postpone colonoscopy in young adult \u003cem\u003epath_PMS2\u003c/em\u003e carriers until 35 years of age should be questioned. Second, since undertaking colonoscopy more frequently than every three years may not reduce CRC incidences in \u003cem\u003epath_MLH1\u003c/em\u003e and \u003cem\u003epath_MSH2\u003c/em\u003e carriers, the rationale for more frequent colonoscopies should be questioned. Third, the very minor fraction of \u003cem\u003epath_MMR\u003c/em\u003e carriers who have multiple adenomas will be identified at colonoscopy and may be followed more intensively. The driving forces causing their multiple adenomas remain unclear, and empirical knowledge on effects of interventions in this group are limited.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe PLSD was designed to address why colonoscopy with polypectomy did not reduce CRC incidence as had been assumed by accelerated adenoma-carcinoma model for CRC in \u003cem\u003epath_MMR\u003c/em\u003e carriers. Based on combined and concomitant epidemiological and biological findings we propose an alternative model in which there is an accelerated chaotic stochastic pathway to MSI CRC from the dMMR crypt which may cause invasive tumours with no or short sojourn time in adenoma stage. We note, with interest and excitement, that in addition to its applicability in CRC, our model may be relevant to the much wider spectrum of cancers that characterise the four Lynch syndromes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePM, EH and MD-V received a grant from The Norwegian Cancer Society, Contract 194751-2017. TTS received grants from Cancer Society Finland, Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, Relander Foundation and the Academy of Finland. DGE is funded by the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007), IS-BRC-1215-20007.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe tables are the raw data grouped as indicated. Figure 1 is based on Table 2. The complete SQL code for how the grouped data underlying Figure 3 was extracted from the MySQL database is published in reference #22. Anonymized data underlying Figure 2, the annual incidences by age group underlying figure 3 are available upon request, both pending written agreement that none of these will be used for any other purpose than confirming the figures to be correct.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePM designed the study, calculated the results and drafted the paper. PM, SH, AA, MK, JRS and LS together developed the suggested model for carcinogenesis. All authors substantially contributed to the conception and design of the final manuscript and/or revised it for intellectual content and approved it.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEHTG is a charitable company registration number SC048407 in Scotland. EHTG is the legal host for PLSD. Anyone may contribute to and become part of the PLSD \u0026ndash; for details see www.ehtg.org .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent for publishing data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eToni T. Sepp\u0026auml;l\u0026auml;: Healthfund Finland (CEO and stock holding), LS Cancer Diag (advisory board and stock holding) and Amgen Finland (speaker honorarium).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eM\u0026oslash;ller P, Sepp\u0026auml;l\u0026auml; TT, Ahadova A, et al. Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement. Hered Cancer Clin Pract. 2023 Oct 11;21(1):19. doi: 10.1186/s13053-023-00263-3. PMID: 37821984; PMCID: PMC10568908. https://pubmed.ncbi.nlm.nih.gov/37821984/\u003c/li\u003e\n\u003cli\u003ehttps://www.omim.org/ Accessed April 2\u003csup\u003end\u003c/sup\u003e 2024\u003c/li\u003e\n\u003cli\u003eChan TA, Wang Z, Dang LH, Vogelstein B, Kinzler KW. Targeted inactivation of CTNNB1 reveals unexpected effects of beta-catenin mutation. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8265-70. doi: 10.1073/pnas.082240999. 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Am J Epidemiol. 1998 Sep 15;148(6):609-19. doi: 10.1093/oxfordjournals.aje.a009687. PMID: 9753016. https://pubmed.ncbi.nlm.nih.gov/9753016/\u003c/li\u003e\n\u003cli\u003ehttps://en.wikipedia.org/wiki/Poisson_distribution Accessed April 2\u003csup\u003end\u003c/sup\u003e 2024\u003c/li\u003e\n\u003cli\u003ehttps://www.britannica.com/science/stochastic-process Accessed April 2\u003csup\u003end\u003c/sup\u003e 2024\u003c/li\u003e\n\u003cli\u003ehttps://en.wikipedia.org/wiki/Introduction_to_quantum_mechanics Accessed April 2\u003csup\u003end\u003c/sup\u003e 2024\u003c/li\u003e\n\u003cli\u003eAnnelie Liljegren, Gail Barker, Faye Elliott, et al. Polyps in Mismatch Repair Mutation Carriers Among CAPP2 Participants: Report by the Colorectal Adenoma/Carcinoma Prevention Programme 2. JCO 2008; 26; 20; 3434-9 https://ascopubs.org/doi/10.1200/JCO.2007.13.2795\u003c/li\u003e\n\u003cli\u003eAhadova, A., von Knebel Doeberitz, M., Bl\u0026auml;ker, H. \u003cem\u003eet al.\u003c/em\u003e \u003cem\u003eCTNNB1\u003c/em\u003e-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. \u003cem\u003eFamilial Cancer\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 579\u0026ndash;586 (2016). https://doi.org/10.1007/s10689-016-9899-z https://link.springer.com/article/10.1007/s10689-016-9899-z\u003c/li\u003e\n\u003cli\u003eAhadova A, Stenzinger A, Sepp\u0026auml;l\u0026auml; T, H\u0026uuml;neburg R, Kloor M, Bl\u0026auml;ker H; Lynpath Investigators. A \u0026quot;Two-in-One Hit\u0026quot; Model of Shortcut Carcinogenesis in MLH1 Lynch Syndrome Carriers. Gastroenterology. 2023 Jul;165(1):267-270.e4. doi: 10.1053/j.gastro.2023.03.007. Epub 2023 Mar 11. PMID: 36907525. https://pubmed.ncbi.nlm.nih.gov/36907525/\u003c/li\u003e\n\u003cli\u003eHelderman NC, Van Der Werf-\u0026apos;t Lam AS; MSH6 TUMOR GROUP; Morreau H, Boot A, Van Wezel T, Nielsen M. Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome-Associated Colorectal Carcinomas. Gastroenterology. 2023 Jul;165(1):271-274.e2. doi: 10.1053/j.gastro.2023.03.198. Epub 2023 Mar 15. PMID: 36931573. https://pubmed.ncbi.nlm.nih.gov/36931573/\u003c/li\u003e\n\u003cli\u003eTen Broeke SW, van Bavel TC, Jansen AML, et al. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2. Gastroenterology. 2018 Sep;155(3):844-851. doi: 10.1053/j.gastro.2018.05.020. Epub 2018 Jul 29. PMID: 29758216. https://pubmed.ncbi.nlm.nih.gov/29758216/\u003c/li\u003e\n\u003cli\u003ehttps://www.google.com/search?client=firefox-b-d\u0026amp;q=heisenberg+uncertainty+principle Accessed April 2\u003csup\u003end\u003c/sup\u003e 2024\u003c/li\u003e\n\u003cli\u003eStaffa L, Echterdiek F, Nelius N, et al. Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters. PLoS One. 2015 Mar 27;10(3):e0121980. doi: 10.1371/journal.pone.0121980. PMID: 25816162; PMCID: PMC4376900. https://pubmed.ncbi.nlm.nih.gov/25816162/\u003c/li\u003e\n\u003cli\u003eSottoriva, A., Kang, H., Ma, Z. \u003cem\u003eet al.\u003c/em\u003e A Big Bang model of human colorectal tumor growth. \u003cem\u003eNat Genet\u003c/em\u003e \u003cstrong\u003e47\u003c/strong\u003e, 209\u0026ndash;216 (2015). https://doi.org/10.1038/ng.3214 https://www.nature.com/articles/ng.3214\u003c/li\u003e\n\u003cli\u003eChien J, Neums L, Powell AFLA, Torres M, Kalli KR, Multinu F, Shridhar V, Mariani A. Genetic Evidence for Early Peritoneal Spreading in Pelvic High-Grade Serous Cancer. Front Oncol. 2018 Mar 7;8:58. doi: 10.3389/fonc.2018.00058. PMID: 29594039; PMCID: PMC5858520. https://pubmed.ncbi.nlm.nih.gov/29594039/ \u003c/li\u003e\n\u003cli\u003eDominguez-Valentin M, Sepp\u0026auml;l\u0026auml; TT, Sampson JR, et al. Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report. Hered Cancer Clin Pract. 2019 Oct 14;17:28. doi: 10.1186/s13053-019-0127-3. PMID: 31636762; PMCID: PMC6792227. https://pubmed.ncbi.nlm.nih.gov/31636762/\u003c/li\u003e\n\u003cli\u003eMangas-Sanjuan C, de-Castro L, Cubiella J, et al. Role of Artificial Intelligence in Colonoscopy Detection of Advanced Neoplasias : A Randomized Trial. Ann Intern Med. 2023 Sep;176(9):1145-1152. doi: 10.7326/M22-2619. Epub 2023 Aug 29. PMID: 37639723. https://pubmed.ncbi.nlm.nih.gov/37639723/\u003c/li\u003e\n\u003cli\u003eH\u0026uuml;neburg R, Bucksch K, Schmei\u0026szlig;er F, et al. Real-time use of artificial intelligence (CADEYE) in colorectal cancer surveillance of patients with Lynch syndrome-A randomized controlled pilot trial (CADLY). United European Gastroenterol J. 2023 Feb;11(1):60-68. doi: 10.1002/ueg2.12354. Epub 2022 Dec 26. PMID: 36571259; PMCID: PMC9892476. https://pubmed.ncbi.nlm.nih.gov/36571259/\u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez A, Roos VH, Navarro M, et al. Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome. Clin Gastroenterol Hepatol. 2022 Mar;20(3):611-621.e9. doi: 10.1016/j.cgh.2020.11.002. Epub 2020 Nov 3. PMID: 33157315. https://pubmed.ncbi.nlm.nih.gov/33157315/\u003c/li\u003e\n\u003cli\u003eSleiman J, Farha N, Beard J, et al. Incidence and prevalence of advanced colorectal neoplasia in Lynch syndrome. Gastrointest Endosc. 2023 Sep;98(3):412-419.e8. doi: 10.1016/j.gie.2023.04.001. Epub 2023 Apr 7. PMID: 37031913. https://pubmed.ncbi.nlm.nih.gov/37031913/\u003c/li\u003e\n\u003cli\u003eAronson M, Gryfe R, Choi YH, et al. Evaluating colonoscopy screening intervals in patients with Lynch syndrome from a large Canadian registry. J Natl Cancer Inst. 2023 Jul 6;115(7):778-787. doi: 10.1093/jnci/djad058. PMID: 36964717; PMCID: PMC10323893. https://pubmed.ncbi.nlm.nih.gov/36964717/\u003c/li\u003e\n\u003cli\u003eDel Carmen G, Reyes-Uribe L, Goyco D, et al. Colorectal surveillance outcomes from an institutional longitudinal cohort of lynch syndrome carriers. Front Oncol. 2023 Apr 24;13:1146825. doi: 10.3389/fonc.2023.1146825. PMID: 37168379; PMCID: PMC10164917. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10164917/\u003c/li\u003e\n\u003cli\u003eHenry T. Lync, Jane F. Lynch, Robert Fitzgibbons, Jr. Role of Prophylactic Colectomy in Lynch Syndrome. Clinical Colorectal Cancer. 2003,3;2; 99-101August 2003; 99 https://www.sciencedirect.com/science/article/pii/S1533002811700743?via%3Dihub\u003c/li\u003e\n\u003cli\u003eCavestro GM, Mannucci A, Balaguer F, et al. Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines. Clin Gastroenterol Hepatol. 2023 Mar;21(3):581-603.e33. doi: 10.1016/j.cgh.2022.12.006. Epub 2022 Dec 20. PMID: 36549470. https://pubmed.ncbi.nlm.nih.gov/36549470/\u003c/li\u003e\n\u003cli\u003eSepp\u0026auml;l\u0026auml; TT, Latchford A, Negoi I, et al. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. Br J Surg. 2021 May 27;108(5):484-498. doi: 10.1002/bjs.11902. PMID: 34043773; PMCID: PMC10364896. https://pubmed.ncbi.nlm.nih.gov/34043773/\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Number of carriers by sex and gene, average age and number of adenomas with 95% CI, number of adenomas by grade, and total number of adenomas.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"558\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.440860215053764%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.810035842293907%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.21505376344086%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.232974910394265%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up years (mean)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.043010752688172%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean age\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.25806451612903%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of adenomas\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.256983240223462%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.87150837988827%\" valign=\"top\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.87150837988827%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdvanced\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.464991023339318%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePath_MSH2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.822262118491921%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.23339317773788%\" valign=\"top\"\u003e\n \u003cp\u003e574\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.26032315978456%\"\u003e\n \u003cp\u003e6,206\u003c/p\u003e\n \u003cp\u003e(10.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.082585278276483%\" valign=\"top\"\u003e\n \u003cp\u003e53.0 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.43806104129264%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.97 (0.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.8838174273858925%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.825726141078839%\" valign=\"top\"\u003e\n \u003cp\u003e661\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.634854771784234%\"\u003e\n \u003cp\u003e6,689 (10.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003e53.6 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.751037344398341%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e519\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.79 (0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" valign=\"top\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.464991023339318%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePath_MLH1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.822262118491921%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.23339317773788%\" valign=\"top\"\u003e\n \u003cp\u003e649\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.26032315978456%\"\u003e\n \u003cp\u003e8,880 (13.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.082585278276483%\" valign=\"top\"\u003e\n \u003cp\u003e54.4 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.43806104129264%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e519\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.80 (0.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.8838174273858925%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.825726141078839%\" valign=\"top\"\u003e\n \u003cp\u003e719\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.634854771784234%\"\u003e\n \u003cp\u003e10,126 (14.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003e56.0 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.751037344398341%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.76 (0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" valign=\"top\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.464991023339318%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePath_MSH6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.822262118491921%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.23339317773788%\" valign=\"top\"\u003e\n \u003cp\u003e346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.26032315978456%\"\u003e\n \u003cp\u003e2,680 (7.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.082585278276483%\" valign=\"top\"\u003e\n \u003cp\u003e57.0 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.43806104129264%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e311\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.90 (0.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.8838174273858925%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.825726141078839%\" valign=\"top\"\u003e\n \u003cp\u003e426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.634854771784234%\"\u003e\n \u003cp\u003e3,123 (7.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003e56.2 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.751037344398341%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.57 (0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.464991023339318%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePath_PMS2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.822262118491921%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.23339317773788%\" valign=\"top\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.26032315978456%\"\u003e\n \u003cp\u003e415 (4.9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.082585278276483%\" valign=\"top\"\u003e\n \u003cp\u003e56.0 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.43806104129264%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.46 (0.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.8838174273858925%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.825726141078839%\" valign=\"top\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.634854771784234%\"\u003e\n \u003cp\u003e616 (5.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.518672199170126%\" valign=\"top\"\u003e\n \u003cp\u003e52.8 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.751037344398341%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e0.33 (0.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.692946058091286%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.464991023339318%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.822262118491921%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.23339317773788%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.26032315978456%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.082585278276483%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.43806104129264%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.464991023339318%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSum\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.822262118491921%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.23339317773788%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e3,574\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.26032315978456%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e38,735\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.082585278276483%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.43806104129264%\" valign=\"top\" style=\"width: 10.9354%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2,767\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\" style=\"width: 12.1829%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.8491921005386%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e276\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 Number of carriers by gene and sum adenomas, also indicating numbers of adenomas, unclassified polyps, hyperplastic, serrated, juvenile, hamartomas, total number of polyps and average age in group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.303886925795053%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.303886925795053%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.017667844522968%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber adenomas in each carrier in group (row)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.37455830388693%\" colspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of carriers within group (row) with other polyps, by polyp type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.53727506426735%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eunclassified\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.53727506426735%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ehyperplastic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.652956298200515%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eserrated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.652956298200515%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ejuvenile\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.53727506426735%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ehamartomas\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.082262210796916%\" valign=\"top\"\u003e\n \u003cp\u003eMean age\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.274647887323944%\" rowspan=\"15\" valign=\"top\"\u003e\n \u003cp\u003ePath_MLH1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e907\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e53.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e54.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e60.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e63.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e59.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e61.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e67.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e71.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e66.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e40.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e54.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e64.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e57.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e72.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e79.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.274647887323944%\" rowspan=\"15\" valign=\"top\"\u003e\n \u003cp\u003ePath_MSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e812\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e50.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e55.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e57.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e63.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e59.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e68.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e65.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e65.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e64.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e66.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e60.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e57.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e50.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e63.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e80.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.274647887323944%\" rowspan=\"15\" valign=\"top\"\u003e\n \u003cp\u003ePath_MSH6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e53.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e62.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e65.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e64.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e72.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e62.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e64.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e45.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e82.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e74.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e59.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e67.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e80.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e79.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e62.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.274647887323944%\" rowspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003ePath_ PMS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.035211267605634%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.380281690140846%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.274647887323944%\" valign=\"top\"\u003e\n \u003cp\u003e52.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e57.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e62.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e58.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e69.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e56.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.314779270633398%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.940499040307103%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.587332053742802%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.021113243761997%\" valign=\"top\"\u003e\n \u003cp\u003e72.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3 Numbers, follow-up years and prospectively detected CRCs in carriers with and without adenomas in last colonoscopy before CRC; and without CRC before or at first colonoscopy (prevalence round), by genetic variants.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"474\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.573839662447256%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.869198312236287%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.51054852320675%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber carriers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.839662447257385%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.206751054852322%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber CRC\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.573839662447256%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eCarriers with adenoma(s)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.869198312236287%\" valign=\"top\"\u003e\n \u003cp\u003ePath_MLH1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.51054852320675%\" valign=\"bottom\"\u003e\n \u003cp\u003e554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.839662447257385%\" valign=\"bottom\"\u003e\n \u003cp\u003e7,567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.206751054852322%\" valign=\"top\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.62125340599455%\" valign=\"top\"\u003e\n \u003cp\u003ePath_MSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.615803814713896%\" valign=\"bottom\"\u003e\n \u003cp\u003e518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.79019073569482%\" valign=\"bottom\"\u003e\n \u003cp\u003e5,125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.97275204359673%\" valign=\"top\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.62125340599455%\" valign=\"top\"\u003e\n \u003cp\u003ePath_MSH6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.615803814713896%\" valign=\"bottom\"\u003e\n \u003cp\u003e402\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.79019073569482%\" valign=\"bottom\"\u003e\n \u003cp\u003e2,775\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.97275204359673%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.62125340599455%\" valign=\"top\"\u003e\n \u003cp\u003ePath_PMS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.615803814713896%\" valign=\"bottom\"\u003e\n \u003cp\u003e116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.79019073569482%\" valign=\"bottom\"\u003e\n \u003cp\u003e538\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.97275204359673%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.573839662447256%\" valign=\"top\"\u003e\n \u003cp\u003eSum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.869198312236287%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.51054852320675%\" valign=\"top\"\u003e\n \u003cp\u003e1,590\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.839662447257385%\" valign=\"top\"\u003e\n \u003cp\u003e16,005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.206751054852322%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.573839662447256%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.869198312236287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.51054852320675%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.839662447257385%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.206751054852322%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.573839662447256%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eCarriers without adenoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.869198312236287%\"\u003e\n \u003cp\u003ePath_MLH1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.51054852320675%\" valign=\"bottom\"\u003e\n \u003cp\u003e329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.839662447257385%\" valign=\"bottom\"\u003e\n \u003cp\u003e5,778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.206751054852322%\" valign=\"top\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.62125340599455%\"\u003e\n \u003cp\u003ePath_MSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.615803814713896%\" valign=\"bottom\"\u003e\n \u003cp\u003e231\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.79019073569482%\" valign=\"bottom\"\u003e\n \u003cp\u003e3,068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.97275204359673%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.62125340599455%\"\u003e\n \u003cp\u003ePath_MSH6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.615803814713896%\" valign=\"bottom\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.79019073569482%\" valign=\"bottom\"\u003e\n \u003cp\u003e1,134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.97275204359673%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.62125340599455%\"\u003e\n \u003cp\u003ePath_PMS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.615803814713896%\" valign=\"bottom\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.79019073569482%\" valign=\"bottom\"\u003e\n \u003cp\u003e228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.97275204359673%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.573839662447256%\" valign=\"top\"\u003e\n \u003cp\u003eSum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.869198312236287%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.51054852320675%\" valign=\"bottom\"\u003e\n \u003cp\u003e703\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.839662447257385%\" valign=\"bottom\"\u003e\n \u003cp\u003e10,208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.206751054852322%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.573839662447256%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.869198312236287%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.51054852320675%\" valign=\"top\"\u003e\n \u003cp\u003e2,293\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.839662447257385%\" valign=\"top\"\u003e\n \u003cp\u003e26,213\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.206751054852322%\" valign=\"top\"\u003e\n \u003cp\u003e239\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 4 Number having no polyps, adenomas or other polyps (not classified or otherwise classified) detected at last colonoscopy before CRC diagnosed by gene, age at CRC diagnosed, and months since last colonoscopy before CRC was diagnosed.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"425\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.941176470588236%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eadenoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.647058823529411%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.647058823529413%\" valign=\"top\" style=\"width: 21.1691%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean months before (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.764705882352942%\" valign=\"top\" style=\"width: 20.478%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean age (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePath_MLH1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.941176470588236%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.647058823529411%\" valign=\"top\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.647058823529413%\" valign=\"top\" style=\"width: 21.1691%;\"\u003e\n \u003cp\u003e26.7 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.764705882352942%\" valign=\"top\" style=\"width: 20.478%;\"\u003e\n \u003cp\u003e53.1 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.058823529411764%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.05882352941177%\" valign=\"top\" style=\"width: 21.1691%;\"\u003e\n \u003cp\u003e29.4 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.705882352941178%\" valign=\"top\" style=\"width: 20.478%;\"\u003e\n \u003cp\u003e52.7 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePath_MSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.941176470588236%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.647058823529411%\" valign=\"top\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.647058823529413%\" valign=\"top\" style=\"width: 21.1691%;\"\u003e\n \u003cp\u003e35.1 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.764705882352942%\" valign=\"top\" style=\"width: 20.478%;\"\u003e\n \u003cp\u003e52.6 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.058823529411764%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.05882352941177%\" valign=\"top\" style=\"width: 21.1691%;\"\u003e\n \u003cp\u003e27.9 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.705882352941178%\" valign=\"top\" style=\"width: 20.478%;\"\u003e\n \u003cp\u003e54.0 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePath_MSH6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.941176470588236%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.647058823529411%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.647058823529413%\" valign=\"top\" style=\"width: 21.1691%;\"\u003e\n \u003cp\u003e20.6 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.764705882352942%\" valign=\"top\" style=\"width: 20.478%;\"\u003e\n \u003cp\u003e58.8 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.176470588235293%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.058823529411764%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.05882352941177%\" valign=\"top\" style=\"width: 21.1691%;\"\u003e\n \u003cp\u003e28.6 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.705882352941178%\" valign=\"top\" style=\"width: 20.478%;\"\u003e\n \u003cp\u003e52.0 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"hereditary-cancer-in-clinical-practice","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hccp","sideBox":"Learn more about [Hereditary Cancer in Clinical Practice](http://jhoonline.biomedcentral.com)","snPcode":"13053","submissionUrl":"https://submission.nature.com/new-submission/13053/3","title":"Hereditary Cancer in Clinical Practice","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"snapp","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"MSI, MLH1, MSH2, MSH6, PMS2, dMMR, Lynch syndromes, colorectal, cancer, adenoma, colonoscopy, sojourn time","lastPublishedDoi":"10.21203/rs.3.rs-4238470/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4238470/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground:\u003c/p\u003e\n\u003cp\u003eColorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database [PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair [\u003cem\u003epath_MMR\u003c/em\u003e) genes.\u003c/p\u003e\n\u003cp\u003eMaterial and methods:\u003c/p\u003e\n\u003cp\u003eWe examined the CRC and colorectal adenoma incidences in 3,574 \u003cem\u003epath_MLH1, path_MSH2, path_MSH6 \u003c/em\u003eand \u003cem\u003epath_PMS2\u003c/em\u003e carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms.\u003c/p\u003e\n\u003cp\u003eResults:\u003c/p\u003e\n\u003cp\u003eMost of the \u003cem\u003epath_MMR\u003c/em\u003e carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in \u003cem\u003epath_PMS2\u003c/em\u003e carriers.\u003c/p\u003e\n\u003cp\u003eConclusions:\u003c/p\u003e\n\u003cp\u003eColonoscopy prevented CRC in \u003cem\u003epath_PMS2\u003c/em\u003e carriers but not in the others. The findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing adenomas which might otherwise become CRCs. However, in carriers other than \u003cem\u003epath_PMS2\u003c/em\u003e, most CRCs observed in carriers subjected to colonoscopy likely arise from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. This mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.\u003c/p\u003e","manuscriptTitle":"Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-15 10:48:56","doi":"10.21203/rs.3.rs-4238470/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-28T02:29:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-27T08:40:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-15T12:59:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5d870454-2909-4eea-81cc-9485d32ec2a9","date":"2024-04-13T09:27:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2b9f5189-bdb9-40e2-90c5-8602424d1d6f","date":"2024-04-12T09:08:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-11T03:33:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-10T22:36:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-10T07:32:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hereditary Cancer in Clinical Practice","date":"2024-04-08T20:24:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"hereditary-cancer-in-clinical-practice","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hccp","sideBox":"Learn more about [Hereditary Cancer in Clinical Practice](http://jhoonline.biomedcentral.com)","snPcode":"13053","submissionUrl":"https://submission.nature.com/new-submission/13053/3","title":"Hereditary Cancer in Clinical Practice","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"snapp","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9c3e3adb-eda5-40bf-9255-54c0b4394e9b","owner":[],"postedDate":"April 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-05-04T04:40:57+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-15 10:48:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4238470","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4238470","identity":"rs-4238470","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}