Endoscopic surveillance for colorectal cancer and its precursor lesions in Lynch syndrome; time for some policy shifts?

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Romy Noëlle Kuipers, Marissa F Burggraaff, Michiel HJ Maas, Dorien van der Biessen - van Beek, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6100008/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Apr, 2025 Read the published version in Hereditary Cancer in Clinical Practice → Version 1 posted 7 You are reading this latest preprint version Abstract Background: Numerous studies have demonstrated variations in colorectal cancer (CRC) incidence among Lynch Syndrome (LS)-associated mutation carriers, but limited data are available regarding tailoring surveillance- and treatment strategies. Main goal of this study was to estimate whether personalized care could be offered based on respectively germline pathogenic variants ( MLH1 , MSH2 , MSH6 or PMS2 ). Additionally the outcome from patient shared care for early CRC was investigated. Methods: Single center retrospective cohort analysis including patients with one of 4 groups of LS-associated pathogenic variants (PV) ( MLH1 , MSH2 , MSH6 or PMS2 ) who underwent surveillance colonoscopies between January 1978 and February 2024. Analyses were performed to identify differences in precursor lesion- or CRC incidence and treatment among the PVs. Results: From a cohort of 621 LS individuals 496 (133 MLH1 , 107 MSH2 , 180 MSH6 and 76 PMS2 ) could be included in this study. Analyses revealed that, despite adequate surveillance intervals and lower adenoma incidence, individuals with a gPV in MLH1 or MSH2 mutation carriers have higher CRC incidences compared to MSH6 or PMS2. Most detected CRC lesions were early stage T1 CRCs. Treatment for T1 CRC varied considerably, in 68% of the cases deviating from the current golden standard subtotal colectomy, with nearly equivalent recurrence rates. Discussion: Based on higher precursor lesion detection and lower CRC incidences in LS individuals with a gPV in MSH6 or PMS2 under biannual endoscopic surveillance, this study supports the potential for extended surveillance intervals in the latter group. As treatment for the detected T1 CRCs varied considerably with nearly equivalent recurrence rates, it emphases the feasibility of less invasive interventions for LS individuals. Lynch syndrome adenomatous polyps colorectal cancer endoscopic surveillance T1 colorectal cancer Figures Figure 1 Figure 2 INTRODUCTION Lynch syndrome (LS) is an autosomal dominant cancer susceptibility disorder arising from germline pathogenic variants (gPV) in one of the four mismatch repair (MMR) genes. 1 Approximately 42% of the LS patients carry gPVs in MLH1 , 33% in MSH2 , 18% in MSH6 and 7.5% in PMS2 2 . Individuals with a gPV in one of the MMR genes face a hereditary increased risk of developing cancer, in particular early-onset colorectal cancer (CRC) and endometrial cancer. 3 , 4 The lifetime risk on developing CRC differs per gPV, ranging from 40–50% for patients carrying gPVs in MLH1 or MSH2 genes to 10–20% in MSH6 and PMS2 genes. 5 , 6 In an attempt to reduce CRC incidence, all LS patients are offered endoscopic surveillance. 7 , 8 Since the detection of the first LS related mutations in the mid-1990s, surveillance is regulated in guidelines. In earlier years surveillance was based on family history and/or expert opinion of the medical doctor. The aim of endoscopic surveillance is first of all timely removal of precursor lesions from which CRC may eventually arise, and in addition to enable earlier detection of CRC, thereby facilitating early intervention. 7 , 8 Most current guidelines advise to perform surveillance colonoscopies every two years, regardless of mutation type. 7 , 8 Although biennial surveillance has led to significant improvements in LS prognosis 9 , adherence to timely colonoscopy surveillance is suboptimal 10 , 11 , most likely due to patients’ perceived barriers regarding colonoscopies such as discomfort and time consumption. 11 – 13 With the knowledge that substantial differences in CRC incidence exist among the different MMR mutations types 5 , 6 , a potential for less invasive and more personalized surveillance strategies for certain patient groups exist. Limited data support the extension of surveillance intervals for carriers of pathogenic variants MSH6 and PMS2 7 , who are proven to carry lower cumulative CRC incidences, possible due to another tumor biology. 14 There is ongoing debate about the optimal treatment protocol for patients with LS. Current Dutch guidelines recommend all patients to undergo subtotal colectomy upon detection of CRC during surveillance. 11 The latest European guideline from the European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) suggests that, given the relatively low lifetime risk of developing CRC and metachronous CRC, more bowel-conserving therapies should be considered for MSH6 and PMS2 mutation carriers, such as partial colectomies. 5 In daily practice, variability exists ranging from performing partial colectomies to even local endoscopic resections 15 , possibly due to the increased detection of early-stage lesions through frequent surveillance. 9 , 16 , 17 Uncertainty surrounds the optimal approach for treating T1 CRC in LS patients, including whether local treatment or surgical intervention is preferable, and which option yields the lowest recurrence rates. 18 , 19 During the last 5 to 10 years for LS two big data cohorts have been developed. One big data cohort origins from the InSIGHT ( https://insight-database.org/ ), estimating cancer risks based on specific variants. Additionally recently the Prospective Lynch Syndrome Database (PLSD, https://plsd.eu/ ) was developed. In this database surveillance data from about 6000 LS carriers have been collected, from which cancer incidences per affected gene, gender and age are presented. Both databases are filled by individual caretaker, without check on accuracy and completeness. Also these data origin from many hospitals with often only a few per hospital included. As such there is a risk for an unknows treatment variation. Both InSIGHT and PLDS do not report advanced neoplasia, second and third CRCs and treatment (variation). Understanding whether specific Lynch-associated PVs exhibit differential detection rates of CRC as well as evaluating existing treatment modalities can be of additional value for tailoring surveillance- and treatment strategies. Aim of this single center study is to evaluate both occurrence and management of CRC and its precursor lesions during surveillance across patients with LS with a gPV in a different MMR-gene.. The findings of this study may contribute to shape risk stratification, surveillance- and treatment protocols, ultimately leading to more personalized interventions and improved outcomes for LS patients. METHODS Study design This retrospective cohort analysis was conducted at the Radboud university medical centre in Nijmegen, the Netherlands. Patients that underwent surveillance colonoscopies for LS between January 1978 and February 2024 were screened for eligibility. Patients that were eligible to include in the study were stratified into four groups according to their PV status. The study was ethical approved by the ‘Central Committee on Research involving Human subjects’ dossier number '2023–16812'. Study population Every patient who carried one of the LS-associated PVs ( MLH1 , MSH2 , MSH6 or PMS2 ) and underwent at least one surveillance colonoscopy after their index colonoscopy between January 1978 and February 2024 could be included. Patients were excluded once they carried multiple LS-associated PVs, received an experimental LS vaccination or underwent colectomy without available information regarding the procedure. Data collection Baseline characteristics such as age, sex and PV type were extracted from electronic health records. In addition, information regarding the performed surveillance colonoscopies, corresponding pathology reports and performed treatment was gathered. All data were checked by two researchers (MB and TB). Outcomes The primary outcome consisted of incidences of precursor lesions and CRC among the different PVs during the surveillance period. In addition, we also evaluated the various treatment modalities in case early stage (T1) CRC was detected. Secondary outcomes involved variations among mutation groups in TNM-staging of the identified CRCs and anatomical locations of precursor lesions. Statistical analysis In this study, a p-value of < 0.05 was considered statistically significant and 95% confidence intervals (CI) were presented when appropriate. Data analyses were performed with the use of IBM SPSS Statistics for Windows, version 29.0. All data were reported as mean with standard deviation (SD) or median with interquartile range (IQR). Categorial outcomes were presented as count with percentages. Differences between mutation variants were analysed using Chi-square, Fisher-Freeman-Halton exact, one way ANOVA or Kruskal Wallis tests. Kaplan Meier time-to-event analyses with log-rank tests were performed to calculate cumulative incidence of CRC, after which cox regression analyses with corresponding hazard ratios (HR) and 95% CIs were performed to evaluate variations between the mutation groups. RESULTS A total of 632 LS individuals were assessed for eligibility of which 604 individuals were confirmed carriers of gPVs in MMR genes. Of those, 108 matched exclusion criteria ultimately leading to the inclusion of 496 LS individuals; 133 in the MLH1 group, 107 in the MSH2 group, 180 in the MSH6 group and 76 in the PMS2 group (Fig. 1 ). Several baseline characteristics differed between the groups (Table 1 ). Individuals carrying the MLH1 or MSH2 gPV were younger at time of LS diagnosis compared to those carrying MSH6 and PMS2 gPVs with a median age of 34 and 35 versus 41 and 48 years (p < 0.001), respectively. Surveillance period of individuals in the MLH1 and MSH2 group was longer compared to those in the MSH6 and PMS2 group (10 and 15 years vs. 7 and 6 years; p < 0.001). In MLH1 and MSH2 more surveillance coloscopies were performed (8 and 8 vs. 5 and 4; p < 0.001) and the mean interval between the procedures was shorter (1.7 and 1.9 years vs. 2.0 and 2.0 years; p = 0.007). Moreover, a significantly higher incidence of CRC was found during initial colonoscopy within the MLH1 group (17%), in contrast to the MSH2 (8%), MSH6 (5%) or PMS2 group (7%; p = 0.004). No differences in detection of precursor lesions during initial colonoscopy were observed across the groups. Table 1 Baseline characteristics MLH1 (n = 133) MSH2 (n = 107) MSH6 (n = 180) PMS2 (n = 76) P-value Sex (male) 61 (46%) 50 (47%) 71 (39%) 35 (46%) 0.542 Age (years) 52 (37–63) 50 (40–62) 53 (42–66) 55 (46–68) 0.036* Age LS diagnosis 34 (26–47) 35 (27–48) 41 (33–54) 48 (39–55) < 0.001* Age first CRC 46 (12) 46 (13) 47 (12) 45 (13) 0.963 Lesions found during initial colonoscopy Non-advanced adenomas 23 (17%) 18 (17%) 39 (22%) 14 (18%) 0.698 Advanced adenomas 3 (2%) 3 (3%) 6 (3%) 2 (3%) 0.980 CRC 22 (17%) 9 (8%) 9 (5%) 5 (7%) 0.004* Total surveillance period (years) 10 (5–19) 15 (5–19) 7 (4–13) 6 (2–10) < 0.001* Performed colonoscopies 8 (4–13) 8 (4–13) 5 (3–8) 4 (2–6) < 0.001* Surveillance interval (years) 1.7 (1.3–2.2) 1.9 (1.5–2.2) 2.0 (1.7–2.2) 2.0 (1.8–2.3) 0.007* Data are mean (SD) or median (IQR) and n (%). LS = Lynch syndrome. CRC = colorectal cancer. Advanced adenomas are defined as adenomas > 10mm or with high-grade dysplasia. Non-advanced adenomas are adenomas < 10mm and without high-grade dysplasia. Individuals carrying gPVs in MLH1 and MSH2 showed significantly higher cumulative lifetime incidences of CRC compared to MSH6 (p < 0.001; p = 0.021; Fig. 2 ). In MLH1 more CRCs were detected in men (n = 16/61, 26%) compared to women (n = 6/72, 8%). Individuals with a MLH1 gPV also showed significantly higher cumulative lifetime incidences of CRCs compared to PMS2 (p = 0.012) gPV carriers. In terms of life-time CRC risks, individuals within the MLH1 group and MSH2 group exhibited higher life-time risks compared to individuals in the MSH6 group with HRs of 3.5 (95% CI 1.8–6.7) and 2.4 (95% CI 1.2–4.9), respectively. Individuals in the MLH1 group also showed a significantly higher lifetime CRC risk compared to those in the PMS2 group (HR 3.4; 95% CI 1.3–8.7). Eighteen individuals with LS caused by a gPV in one of the MMR genes had two CRCs outside the surveillance setting. In seven of them this concerned synchronous cancers (1 MLH1, 4 MSH2, 2 MSH6). Eleven of them had the first CRC in the 80’s or early 90’s. In all of them a Lynch PV was found after detection of the second CRC. None of them had a third CRC during surveillance afterwards. Non-advanced adenomas were most frequently detected throughout the surveillance period (89%), with a significant difference between the groups showing higher incidences of non-advanced adenomas in MSH6 (96%) and PMS2 (94%) compared to MLH1 (87%) and MSH2 (84%) (p = 0.001; Table 2 ). CRC was identified in 5% of the individuals with LS during the surveillance period. Stratified upon mutation type, individuals in the MLH1 and MSH2 group developed CRC more often with incidences of 8% and 7%, while only 2% of the individuals in the MSH6 group and PMS2 group developed CRC. With regard to location, lesions were most often located right-sided (Table 2 ). Table 2 Surveillance colonoscopies Total (n = 496) MLH1 (n = 133) MSH2 (n = 107) MSH6 (n = 180) PMS2 (n = 76) P-value Lesions detected during surveillance Non-advanced adenoma 569 (89%) 167 (87%) 177 (84%) 173 (96%) 50 (94%) 0.001* Advanced adenoma 69 (11%) 21 (11%) 29 (14%) 13 (7%) 6 (11%) 0.225 Colorectal carcinoma 32 (5%) 15 (8%) 14 (7%) 3 (2%) 1 (2%) 0.024* Location of non-advanced adenoma 0.518 Right-sided 306 (54%) 98 (59%) 87 (49%) 89 (51%) 31 (62%) Left-sided 194 (34%) 52 (31%) 67 (38%) 62 (36%) 13 (26%) Right and Left- sided 68 (12%) 17 (10%) 23 (13%) 22 (13%) 6 (12%) Location of advanced adenomas 0.089 Right-sided 38 (55%) 12 (57%) 12 (41%) 9 (69%) 5 (83%) Left-sided 30 (44%) 9 (43%) 17 (59%) 3 (23%) 1 (17%) Right and Left- sided 1 (1%) 0 (0%) 0 (0%) 1 (8%) 0 Location of CRC 0.355 Right-sided 23 (70%) 12 (80%) 9 (64%) 2 (67%) 0 Left-sided 9 (30%) 3 (20%) 5 (36%) 1 (33%) 1 (100%) Data are median (IQR) and n (%). CRC = colorectal cancer. Advanced adenomas are defined as adenomas > 10mm or with high-grade dysplasia. Non-advanced adenomas are adenomas < 10mm and without high-grade dysplasia. Lesions are considered right-sided when located proximal of the splenic flexure. Lesions are considered left sided when located distal of the splenic flexure. As shown in Table 3 , the majority of CRCs identified during surveillance were classified as T1-stage tumours (52%) and none were classified as T4-stage tumours. The vast majority did not exhibit lymph node (85%) or distant metastases (97%). No significant differences in TNM stages were found among the various mutation groups. Individuals with LS who developed T1 CRC during life underwent subtotal colectomy in 32% of the cases, while partial colectomy and local treatment was performed in 32% and 36% (Table 4 ). Among those with T1 CRC detected during surveillance and in whom treatment deviated from the golden standard, in one of them a second carcinoma was detected. This individual had a T1 rectum carcinoma during his index coloscopy, which was treated by a low anterior resection. The second CRC was found in the ascending colon 12 years later. No metastases were detected and this CRC was adequately resected by a right hemicolectomy. During the follow up 13 years hereafter no third CRC has been detected in this individual. Table 3 TNM stadia of detected CRCs. Total (n = 78) MLH1 (n = 37) MSH2 (n = 23) MSH6 (n = 12) PMS2 (n = 6) P-value Tumor 0.151 Intramucosal 1 (3%) 0 0 1 (8%) 0 T1 (%) 25 (32%) 10 (27%) 12 (52%) 1 (8%) 2 (33%) T2 (%) 19 (24%) 11 (30%) 4 (17%) 3 (25%) 1 (17%) T3 (%) 27 (35%) 11 (30%) 7 (30%) 7 (58%) 2 (33%) T4 (%) 3 (4%) 3 (8%) 0 0 0 Node 0.283 N0 (%) 57 (73%) 29 (78%) 18 (78%) 7 (58%) 3 (50%) N1 (%) 11 (14%) 3 (8%) 4 (17%) 3 (25%) 1 (17%) N2 (%) 7 (9%) 3 (8%) 1 (4%) 2 (17%) 1 (17%) Metastasis 0.122 M0 (%) 74 (95%) 35 (95%) 23 (100%) 11 (92%) 5 (83%) M1 (%) 1 (1%) 0 0 1 (8%) 0 Table 4 Incidences of performed treatments for T1 CRC removal in Lynch patients. Total (n = 25) MLH1 (n = 10) MSH2 (n = 12) MSH6 (n = 1) PMS2 (n = 2) P-value 0.945 Subtotal colectomy 8 (32%) 4 (40%) 4 (33%) 0 0 Partial colectomy 8 (32%) 3 (30%) 3 (25%) 1 (100%) 1 (50%) Local endoscopic treatment 9 (36%) 3 (30%) 5 (42%) 0 1 (50%) Data are n (%).CRC = colorectal cancer. DISCUSSION Numerous studies demonstrated variations in CRC incidence among different LS-associated genes, but limited knowledge exists regarding customization of surveillance- and treatment strategies accordingly. Therefore, our analysis aimed to explore variations in occurrence and management of CRC and its precursor lesions during surveillance across different LS gPV groups. We showed, in accordance with current knowledge 20 , that individuals with a gPV in MLH1 and MSH2 have higher life-time risks to develop CRC compared to MSH6 . In MLH1 the CRC risk is increased in men compared to women. Furthermore, we confirmed that in MLH1 and MSH2 CRC less often develops from visible precursor lesions, whereas in MSH6 and PMS2 significantly more visible precursor lesions are detected. Additionally we observed a considerable variation in performed treatments for T1 CRC. This study possesses several strengths. To our knowledge, it it represents one of the largest single center LS surveillance cohorts with complete surveillance data included. It reports CRC detection rates during surveillance across four different LS associated gPVs over a span of four decades. Additionally, apart from the CRC incidence, the incidence of precursor lesions, metachronous CRCs, TNM stadium from all CRCs and treatment strategies were analyzed. In contrast to prior research, this study only included individuals with confirmed LS-associated gPVs. Included individuals were under surveillance at a specialized LS centre staffed with experienced endoscopists. Lastly, to guarantee optimal quality all data were double checked, limiting the risk of information bias. Big data databases, such as InSIGHT and PLDS, identify patterns and as such are useful as prediction models. They are determined by a tenfold of LS carriers compared to our single center cohort. Limitations of the PLDS database are first that the division between the four genes is skewed. As a result the presented MSH6 and PMS2 must be interpreted with caution. Also, the data from the large databases origin from many hospitals each including a considerably lower number of LS carriers compared to our cohort. InSIGHT and PLDS data are reported by the consulting specialists without double check. This might cause selection and reporting bias. Last precursor lesions and treatment variations are not reported in these databases. This study also exhibits several limitations. The retrospective design unavoidably resulted in missing data. However, despite the amount of missing data, significant differences or trends could be observed. Second, timing of precursor and carcinoma detection relied on the timing of colonoscopy procedures, possibly introducing information bias. In addition, improvements of imaging quality over time may have influenced lesion detection, potentially resulting in a higher number of lesions being detected in patients under surveillance nowadays compared to those monitored in the past. Though, in our cohort, as many as 69% of the individuals with LS have been under surveillance during the last 15 years, indicating that the majority of individuals with LS have been monitored with the most modern endoscopic equipment. Both timing of colonoscopy procedures as well as improvements in imaging quality could have possibly affected the overall detection rate. However, it is not expected these limitations would have directly influenced the proportion of detected lesions among mutation groups, as patients undergo similar surveillance protocols. Last a disadvantage of our single center design is that an extension of these findings to the wider group of individuals with LS worldwide might be under dispute. Performing biennial surveillance colonoscopies in individuals with LS has been shown to be essential, as it substantially improved the prognosis of individuals with LS caused by a gPV in one of the MMR genesdue to earlier detection of CRC and premalignant adenomas. 9 However, effectiveness of the surveillance program heavily relies on adherence, and several studies already demonstrated adherence to timely colonoscopy surveillance in individuals with LS is not optimal. 10 , 11 In a study of Van Liere et al. 21 , it was shown that 57% of individuals with LS perceived the surveillance program as extremely burdensome, with even 10% considering quitting surveillance. Many individuals (60%) preferred a less invasive surveillance method. The current biennial surveillance program is thus clearly negatively influencing quality of life, especially if biennial checks may not even be necessary for certain LS associated gPV groups. Earlier studies have already demonstrated variability in the lifetime risks of developing CRC among different individuals with LS, with carriers of a gPV in MLH1 and MSH2 being at highest hereditary CRC riske 20 . Consistently, in this study, we observed that MLH1 exhibited significantly higher CRC incidences at initial colonoscopy compared to other LS-associated gPV groups (Table 1 ). In addition, with regard to detected lesions during surveillance colonoscopies, higher CRC incidences were observed in the MLH1 and MSH2 compared to the MSH6 and PMS2 . At the same time the observed non-advanced adenoma incidence was lower in MLH1 and MSH2. This is in accordance with the most recent knowledge on CRC pathways in LS suggesting three different pathways. 22 It is suggested that CRC development in MLH1 and MSH2 follows a more accelerated pathway with MMR deficient precursor foci in de colonic crypts. 22 In MLH1 these foci might be located under the mucosal layer and as such might be easily overlooked. 23 The observed cumulative lifetime CRC incidence was higher in the MLH1 compared to MSH6 and PMS2 , as well as the cumulative lifetime CRC incidence of MLH2 compared to MSH6 (Fig. 2 ). These findings therefore suggest that, given the substantially lower lifetime risk of developing CRC and considering the negative impact of biennial surveillance on quality of life, surveillance intervals of MSH6 and PMS2 individuals could potentially be safely extended. We additionally investigated differences in TNM staging across the differentgPV groups and the corresponding performed treatments for early-stage CRC. As could be expected from the implementation of biennial surveillance 7 , 8 , most CRCs detected during surveillance colonoscopies were T1 CRCs (52%) without the presence of lymph node- (85%) and distant (97%) metastasis (Table 3 ). When examining the relatively small amount of patients with treated early-stage colorectal T1 CRCs (n = 25), we observed considerable variation in performed treatments (Table 4 ). In 68% of the patients, physicians decided to deviate from the current guideline which recommends to perform subtotal colectomies for early stage CRC. 7 , 8 Less invasive local endoscopic treatment was performed more frequently than the golden standard (36% vs. 32%), clearly demonstrating preference and confidence in more local methods of treatment. Given the significant advancement in endoscopic techniques 24 , 25 and improved functional outcome after more local treatments 26 , it is not surprising there has been growing preference for minimally invasive interventions in recent years. The current guideline for non-LS related colorectal T1 tumors 27 even already includes more tailored treatment recommendations, with endoscopic techniques considered superior to surgical resection in most cases. Specific histological risk factors have been identified for non-LS related colorectal T1 CRCs, including poor differentiation, lymph angioinvasion and high-grade tumor budding, which can predict the risk on metastases and recurrence in non-LS related colorectal T1 tumors. 28 After endoscopic removal of non-LS related colorectal T1 CRCs, the presence or absence of these histological risk factors can subsequently assist in determining the need for additional surgical resection and/or in formulating the appropriate surveillance strategy. 27 Interestingly, only one of the LS patients treated for T1-stage CRC experienced a recurrence twelve years after a CRC was detected during the index colonoscopy, suggesting less invasive organ preserving treatment for LS-related colorectal T1 CRCs might also be a viable option. Nonetheless, evaluation of recurrence rates on the long-term is necessary given that local treatments were conducted more recently, leaving the possibility for recurrences to emerge. In our opinion, future studies should focus on distinguishing more personalized surveillance intervals for different LS associated gPV groups, possibly enabling extension of surveillance intervals for MSH6 and/or PMS2 given the smaller lifetime risks on developing CRC. Regarding treatment strategies for colorectal T1 CRCs, it is crucial to validate these findings in larger patients cohorts, with particular emphasis on monitoring the long-term outcomes of performed endoscopic treatments. In addition, it is interesting to investigate whether the current histological risk factors for non-LS related colorectal T1 CRCs also apply to LS-related colorectal T1 CRCs, and if so, whether these risk factors may vary across the different LS associated gPV groups. In conclusion, this large single center analysis showed a higher precursor lesion detection rate as well as a lower CRC incidences for individuals with LS caused by a gPV in MSH6 or PMS2 , suggesting the potential for extended surveillance intervals for these patients. Furthermore, consistent with biennial surveillance protocols, the majority of CRCs detected during surveillance were T1 CRCs without metastases. Regarding treatment of these T1 CRCs, considerable variation was observed with nearly equivalent recurrence rates, emphasizing the feasibility of less invasive endoscopic interventions for individuals with LS. To refine surveillance strategies, further investigation into extending surveillance intervals for individuals with LS caused by a gPV in MSH6 and PMS2 is needed. Additionally, assessing the long-term outcomes of diverse treatment modalities and identifying histological risk factors specific to LS-related colorectal T1 CRCs are essential steps towards optimizing treatment for LS individuals in the future. Declarations Funding No funding was received for conducting this study. Conflict of interest The authors have no competing interests to declare that are relevant to the content of this article. Contributions Romy N Kuipers & Marissa F Burggraaff (First Authors): Methodology; analysis, writing – original draft; Michiel HJ Maas (Author 2): Analysis, supervision, writing - review & editing; Dorien van der Biessen – van Beek (Author 3): Gathering data, Writing – Review & editing; Mariëtte C van Kouwen (Author 4): Writing - Review & editing; Tanya M Bisseling (senior author): Conceptualization; data curation; supervision; writing – review & editing. References Lynch HT, De la Chapelle A. Hereditary colorectal cancer. 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Best Pract Res Clin Gastroenterol 2023;66:101854. Dekkers N, Dang H, van der Kraan J, le Cessie S, Oldenburg PP, Schoones JW, Langers AMJ, van Leerdam ME, van Hooft JE, Backes Y and others. Risk of recurrence after local resection of T1 rectal cancer: a meta-analysis with meta-regression. Surg Endosc 2022;36(12):9156-9168. Wang C, Wang Y, Hughes KS, Parmigiani G, Braun D. Penetrance of colorectal cancer among mismatch repair gene mutation carriers: a meta-analysis. JNCI Cancer Spectrum 2020;4(5):pkaa027. van Liere EL, Jacobs IL, Dekker E, Jacobs MA, de Boer NK, Ramsoekh D. Colonoscopy surveillance in Lynch syndrome is burdensome and frequently delayed. Familial Cancer 2023;22(4):403-411. Aysel Ahadova, Richard Gallon, Johannes Gebert, Alexej Ballhausen, Volker Endri, Martina Kirchne, Albrecht Stenzinger, John Burn, Magnus von Knebel Doeberitz, Hendrik Blaker and Matthias Kloor. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int. J. Cancer: 143, 139–150 (2018) Christoph Engel, Aysel Ahadova, Toni T. Seppälä, Stefan Aretz, Marloes Bigirwamungu-Bargeman, Hendrik Bläker, Karolin Bucksch, Reinhard Büttner, Wouter T. de Vos tot Nederveen Cappel, Volker Endris, Elke Holinski-Feder, Stefanie Holzapfel, Robert Hüneburg,Maarten A. J. M. Jacobs, Jan J. Koornstra, Alexandra M. Langers, Anna Lepistö, Monika Morak, Gabriela Möslein, Päivi Peltomäki, Kirsi Pylvänäinen, Nils Rahner, Laura Renkonen-Sinisalo, Karsten Schulmann, Verena Steinke-Lange, Albrecht Stenzinger, Christian P. Strassburg, Paul C. van de Meeberg, Mariette van Kouwen, Monique van Leerdam, Deepak B. Vangala, Juda Vecht, Marie-Louise Verhulst, Magnus von Knebel Doeberitz, Jürgen Weitz, Silke Zachariae, Markus Loeffler, Jukka-Pekka Mecklin, Matthias Kloor and Hans F. Vasen on behalf of the German HNPCC Consortium, the Dutch Lynch Syndrome Collaborative Group, and the Finnish Lynch Syndrome Registry. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology 2020;158:1326–1333 Rudiman R. Advances in gastrointestinal surgical endoscopy. Annals of Medicine and Surgery 2021;72:103041. Rashid MU, Alomari M, Afraz S, Erim T. EMR and ESD: Indications, techniques and results. Surgical Oncology 2022;43:101742. Haanstra JF, tot Nederveen WHdV, Gopie JP, Vecht J, Vanhoutvin SA, Cats A, van der Zaag-Loonen HJ, Langers AM, Bergmann JH, van de Meeberg PC. Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy. Diseases of the colon & rectum 2012;55(6):653-659. FM S. Richtlijn Colorectaal Carcinoom (CRC). 2020. Ferlitsch M, Moss A, Hassan C, Bhandari P, Dumonceau J-M, Paspatis G, Jover R, Langner C, Bronzwaer M, Nalankilli K. Colorectal polypectomy and endoscopic mucosal resection (EMR): European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy 2017;49(03):270-297. Additional Declarations No competing interests reported. Supplementary Files Supplementarytablegender20250223.docx Cite Share Download PDF Status: Published Journal Publication published 16 Apr, 2025 Read the published version in Hereditary Cancer in Clinical Practice → Version 1 posted Editorial decision: Revision requested 20 Mar, 2025 Reviews received at journal 09 Mar, 2025 Reviewers agreed at journal 04 Mar, 2025 Reviewers invited by journal 04 Mar, 2025 Editor assigned by journal 27 Feb, 2025 Submission checks completed at journal 27 Feb, 2025 First submitted to journal 24 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6100008","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":421775154,"identity":"85307d8e-ea79-47a2-a2fa-3881cd462d0f","order_by":0,"name":"Romy Noëlle Kuipers","email":"","orcid":"","institution":"Radboud university medical center","correspondingAuthor":false,"prefix":"","firstName":"Romy","middleName":"Noëlle","lastName":"Kuipers","suffix":""},{"id":421775155,"identity":"c98a3ee5-20d3-4784-9f0d-115b7ec84389","order_by":1,"name":"Marissa F Burggraaff","email":"","orcid":"","institution":"Radboud university medical center","correspondingAuthor":false,"prefix":"","firstName":"Marissa","middleName":"F","lastName":"Burggraaff","suffix":""},{"id":421775156,"identity":"013d17e6-16f9-4384-88ac-55b5ad558f32","order_by":2,"name":"Michiel HJ Maas","email":"","orcid":"","institution":"Radboud university medical center","correspondingAuthor":false,"prefix":"","firstName":"Michiel","middleName":"HJ","lastName":"Maas","suffix":""},{"id":421775163,"identity":"28975c23-529f-4673-a14f-9648b4ae3e13","order_by":3,"name":"Dorien van der Biessen - van Beek","email":"","orcid":"","institution":"Radboud university medical center","correspondingAuthor":false,"prefix":"","firstName":"Dorien","middleName":"van der Biessen - van","lastName":"Beek","suffix":""},{"id":421775164,"identity":"3903b710-dd9f-42a9-a6e8-c536154dc91f","order_by":4,"name":"Mariëtte C van Kouwen","email":"","orcid":"","institution":"Radboud university medical center","correspondingAuthor":false,"prefix":"","firstName":"Mariëtte","middleName":"C van","lastName":"Kouwen","suffix":""},{"id":421775165,"identity":"ee7bcda7-53a6-4961-885b-2a50ad5e6b5e","order_by":5,"name":"Tanya M Bisseling","email":"data:image/png;base64,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","orcid":"","institution":"Radboud university medical center","correspondingAuthor":true,"prefix":"","firstName":"Tanya","middleName":"M","lastName":"Bisseling","suffix":""}],"badges":[],"createdAt":"2025-02-24 22:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6100008/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6100008/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13053-025-00312-z","type":"published","date":"2025-04-16T15:57:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":78139577,"identity":"2cda5d9d-af59-48cf-a09b-08f7a253e38c","added_by":"auto","created_at":"2025-03-10 09:54:18","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":306366,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of inclusion\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6100008/v1/ce3a497c89238c13333520ae.jpeg"},{"id":78139557,"identity":"5bb0dd03-3e97-4bb1-bada-554be5a36324","added_by":"auto","created_at":"2025-03-10 09:54:17","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57830,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative life-time incidence of CRC per mutation group\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6100008/v1/f8e0323435938e56ca5366c8.jpg"},{"id":81050962,"identity":"b318ab0b-c178-47e3-be3e-d2b3ea90d09b","added_by":"auto","created_at":"2025-04-21 16:08:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1153546,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6100008/v1/6e7b013a-2831-4977-a27f-1543175ec45b.pdf"},{"id":78139560,"identity":"85b80f79-b300-42b7-9310-0c1753b34bf3","added_by":"auto","created_at":"2025-03-10 09:54:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":21953,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytablegender20250223.docx","url":"https://assets-eu.researchsquare.com/files/rs-6100008/v1/e7bfdee068529e8c92174113.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Endoscopic surveillance for colorectal cancer and its precursor lesions in Lynch syndrome; time for some policy shifts?","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eLynch syndrome (LS) is an autosomal dominant cancer susceptibility disorder arising from germline pathogenic variants (gPV) in one of the four mismatch repair (MMR) genes.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Approximately 42% of the LS patients carry gPVs in \u003cem\u003eMLH1\u003c/em\u003e, 33% in \u003cem\u003eMSH2\u003c/em\u003e, 18% in \u003cem\u003eMSH6\u003c/em\u003e and 7.5% in \u003cem\u003ePMS2\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e. Individuals with a gPV in one of the MMR genes face a hereditary increased risk of developing cancer, in particular early-onset colorectal cancer (CRC) and endometrial cancer.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The lifetime risk on developing CRC differs per gPV, ranging from 40\u0026ndash;50% for patients carrying gPVs in \u003cem\u003eMLH1\u003c/em\u003e or \u003cem\u003eMSH2\u003c/em\u003e genes to 10\u0026ndash;20% in \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e genes.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn an attempt to reduce CRC incidence, all LS patients are offered endoscopic surveillance.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Since the detection of the first LS related mutations in the mid-1990s, surveillance is regulated in guidelines. In earlier years surveillance was based on family history and/or expert opinion of the medical doctor. The aim of endoscopic surveillance is first of all timely removal of precursor lesions from which CRC may eventually arise, and in addition to enable earlier detection of CRC, thereby facilitating early intervention.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Most current guidelines advise to perform surveillance colonoscopies every two years, regardless of mutation type.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Although biennial surveillance has led to significant improvements in LS prognosis\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, adherence to timely colonoscopy surveillance is suboptimal\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, most likely due to patients\u0026rsquo; perceived barriers regarding colonoscopies such as discomfort and time consumption.\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e With the knowledge that substantial differences in CRC incidence exist among the different MMR mutations types\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, a potential for less invasive and more personalized surveillance strategies for certain patient groups exist. Limited data support the extension of surveillance intervals for carriers of pathogenic variants \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e\u003csup\u003e7\u003c/sup\u003e, who are proven to carry lower cumulative CRC incidences, possible due to another tumor biology.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere is ongoing debate about the optimal treatment protocol for patients with LS. Current Dutch guidelines recommend all patients to undergo subtotal colectomy upon detection of CRC during surveillance.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e The latest European guideline from the European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) suggests that, given the relatively low lifetime risk of developing CRC and metachronous CRC, more bowel-conserving therapies should be considered for \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e mutation carriers, such as partial colectomies.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e In daily practice, variability exists ranging from performing partial colectomies to even local endoscopic resections\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, possibly due to the increased detection of early-stage lesions through frequent surveillance.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Uncertainty surrounds the optimal approach for treating T1 CRC in LS patients, including whether local treatment or surgical intervention is preferable, and which option yields the lowest recurrence rates.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDuring the last 5 to 10 years for LS two big data cohorts have been developed. One big data cohort origins from the InSIGHT (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://insight-database.org/\u003c/span\u003e\u003cspan address=\"https://insight-database.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), estimating cancer risks based on specific variants. Additionally recently the Prospective Lynch Syndrome Database (PLSD, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://plsd.eu/\u003c/span\u003e\u003cspan address=\"https://plsd.eu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was developed. In this database surveillance data from about 6000 LS carriers have been collected, from which cancer incidences per affected gene, gender and age are presented. Both databases are filled by individual caretaker, without check on accuracy and completeness. Also these data origin from many hospitals with often only a few per hospital included. As such there is a risk for an unknows treatment variation. Both InSIGHT and PLDS do not report advanced neoplasia, second and third CRCs and treatment (variation). Understanding whether specific Lynch-associated PVs exhibit differential detection rates of CRC as well as evaluating existing treatment modalities can be of additional value for tailoring surveillance- and treatment strategies.\u003c/p\u003e \u003cp\u003eAim of this single center study is to evaluate both occurrence and management of CRC and its precursor lesions during surveillance across patients with LS with a gPV in a different MMR-gene.. The findings of this study may contribute to shape risk stratification, surveillance- and treatment protocols, ultimately leading to more personalized interventions and improved outcomes for LS patients.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis retrospective cohort analysis was conducted at the Radboud university medical centre in Nijmegen, the Netherlands. Patients that underwent surveillance colonoscopies for LS between January 1978 and February 2024 were screened for eligibility. Patients that were eligible to include in the study were stratified into four groups according to their PV status. The study was ethical approved by the \u0026lsquo;Central Committee on Research involving Human subjects\u0026rsquo; dossier number '2023\u0026ndash;16812'.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eEvery patient who carried one of the LS-associated PVs (\u003cem\u003eMLH1\u003c/em\u003e, \u003cem\u003eMSH2\u003c/em\u003e, \u003cem\u003eMSH6\u003c/em\u003e or \u003cem\u003ePMS2\u003c/em\u003e) and underwent at least one surveillance colonoscopy after their index colonoscopy between January 1978 and February 2024 could be included. Patients were excluded once they carried multiple LS-associated PVs, received an experimental LS vaccination or underwent colectomy without available information regarding the procedure.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eBaseline characteristics such as age, sex and PV type were extracted from electronic health records. In addition, information regarding the performed surveillance colonoscopies, corresponding pathology reports and performed treatment was gathered. All data were checked by two researchers (MB and TB).\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome consisted of incidences of precursor lesions and CRC among the different PVs during the surveillance period. In addition, we also evaluated the various treatment modalities in case early stage (T1) CRC was detected.\u003c/p\u003e \u003cp\u003eSecondary outcomes involved variations among mutation groups in TNM-staging of the identified CRCs and anatomical locations of precursor lesions.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eIn this study, a p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant and 95% confidence intervals (CI) were presented when appropriate. Data analyses were performed with the use of IBM SPSS Statistics for Windows, version 29.0. All data were reported as mean with standard deviation (SD) or median with interquartile range (IQR). Categorial outcomes were presented as count with percentages. Differences between mutation variants were analysed using Chi-square, Fisher-Freeman-Halton exact, one way ANOVA or Kruskal Wallis tests. Kaplan Meier time-to-event analyses with log-rank tests were performed to calculate cumulative incidence of CRC, after which cox regression analyses with corresponding hazard ratios (HR) and 95% CIs were performed to evaluate variations between the mutation groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 632 LS individuals were assessed for eligibility of which 604 individuals were confirmed carriers of gPVs in MMR genes. Of those, 108 matched exclusion criteria ultimately leading to the inclusion of 496 LS individuals; 133 in the \u003cem\u003eMLH1\u003c/em\u003e group, 107 in the \u003cem\u003eMSH2\u003c/em\u003e group, 180 in the \u003cem\u003eMSH6\u003c/em\u003e group and 76 in the \u003cem\u003ePMS2\u003c/em\u003e group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral baseline characteristics differed between the groups (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Individuals carrying the \u003cem\u003eMLH1\u003c/em\u003e or \u003cem\u003eMSH2\u003c/em\u003e gPV were younger at time of LS diagnosis compared to those carrying \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e gPVs with a median age of 34 and 35 versus 41 and 48 years (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), respectively. Surveillance period of individuals in the \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e group was longer compared to those in the \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e group (10 and 15 years vs. 7 and 6 years; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e more surveillance coloscopies were performed (8 and 8 vs. 5 and 4; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and the mean interval between the procedures was shorter (1.7 and 1.9 years vs. 2.0 and 2.0 years; p\u0026thinsp;=\u0026thinsp;0.007). Moreover, a significantly higher incidence of CRC was found during initial colonoscopy within the \u003cem\u003eMLH1\u003c/em\u003e group (17%), in contrast to the \u003cem\u003eMSH2\u003c/em\u003e (8%), \u003cem\u003eMSH6\u003c/em\u003e (5%) or \u003cem\u003ePMS2\u003c/em\u003e group (7%; p\u0026thinsp;=\u0026thinsp;0.004). No differences in detection of precursor lesions during initial colonoscopy were observed across the groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMLH1\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;133)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMSH2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;107)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMSH6\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;180)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePMS2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;76)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.542\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (37\u0026ndash;63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (40\u0026ndash;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (42\u0026ndash;66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55 (46\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.036*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge LS diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (26\u0026ndash;47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (27\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (33\u0026ndash;54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48 (39\u0026ndash;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge first CRC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.963\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesions found during initial colonoscopy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-advanced\u003c/p\u003e \u003cp\u003e adenomas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.698\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced\u003c/p\u003e \u003cp\u003e adenomas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.980\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.004*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal surveillance period (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (5\u0026ndash;19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (5\u0026ndash;19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (4\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (2\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerformed \u003c/p\u003e \u003cp\u003e colonoscopies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (4\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (4\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (3\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (2\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurveillance\u003c/p\u003e \u003cp\u003e interval (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.7 (1.3\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.9 (1.5\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0 (1.7\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.0 (1.8\u0026ndash;2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.007*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eData are mean (SD) or median (IQR) and n (%). LS\u0026thinsp;=\u0026thinsp;Lynch syndrome. CRC\u0026thinsp;=\u0026thinsp;colorectal cancer. Advanced adenomas are defined as adenomas\u0026thinsp;\u0026gt;\u0026thinsp;10mm or with high-grade dysplasia. Non-advanced adenomas are adenomas\u0026thinsp;\u0026lt;\u0026thinsp;10mm and without high-grade dysplasia.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIndividuals carrying gPVs in \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e showed significantly higher cumulative lifetime incidences of CRC compared to \u003cem\u003eMSH6\u003c/em\u003e (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; p\u0026thinsp;=\u0026thinsp;0.021; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In MLH1 more CRCs were detected in men (n\u0026thinsp;=\u0026thinsp;16/61, 26%) compared to women (n\u0026thinsp;=\u0026thinsp;6/72, 8%). Individuals with a \u003cem\u003eMLH1\u003c/em\u003e gPV also showed significantly higher cumulative lifetime incidences of CRCs compared to \u003cem\u003ePMS2\u003c/em\u003e (p\u0026thinsp;=\u0026thinsp;0.012) gPV carriers. In terms of life-time CRC risks, individuals within the \u003cem\u003eMLH1\u003c/em\u003e group and \u003cem\u003eMSH2\u003c/em\u003e group exhibited higher life-time risks compared to individuals in the \u003cem\u003eMSH6\u003c/em\u003e group with HRs of 3.5 (95% CI 1.8\u0026ndash;6.7) and 2.4 (95% CI 1.2\u0026ndash;4.9), respectively. Individuals in the \u003cem\u003eMLH1\u003c/em\u003e group also showed a significantly higher lifetime CRC risk compared to those in the \u003cem\u003ePMS2\u003c/em\u003e group (HR 3.4; 95% CI 1.3\u0026ndash;8.7).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEighteen individuals with LS caused by a gPV in one of the MMR genes had two CRCs outside the surveillance setting. In seven of them this concerned synchronous cancers (1 MLH1, 4 MSH2, 2 MSH6). Eleven of them had the first CRC in the 80\u0026rsquo;s or early 90\u0026rsquo;s. In all of them a Lynch PV was found after detection of the second CRC. None of them had a third CRC during surveillance afterwards.\u003c/p\u003e \u003cp\u003eNon-advanced adenomas were most frequently detected throughout the surveillance period (89%), with a significant difference between the groups showing higher incidences of non-advanced adenomas in \u003cem\u003eMSH6\u003c/em\u003e (96%) and \u003cem\u003ePMS2\u003c/em\u003e (94%) compared to \u003cem\u003eMLH1\u003c/em\u003e (87%) and \u003cem\u003eMSH2\u003c/em\u003e (84%) (p\u0026thinsp;=\u0026thinsp;0.001; Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). CRC was identified in 5% of the individuals with LS during the surveillance period. Stratified upon mutation type, individuals in the \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e group developed CRC more often with incidences of 8% and 7%, while only 2% of the individuals in the \u003cem\u003eMSH6\u003c/em\u003e group and \u003cem\u003ePMS2\u003c/em\u003e group developed CRC. With regard to location, lesions were most often located right-sided (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurveillance colonoscopies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;496)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMLH1\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;133)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMSH2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;107)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMSH6\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;180)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePMS2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;76)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesions detected during surveillance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-advanced \u003c/p\u003e \u003cp\u003e adenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e569 (89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e167 (87%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e177 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e173 (96%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50 (94%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdvanced \u003c/p\u003e \u003cp\u003e adenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.225\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColorectal \u003c/p\u003e \u003cp\u003e carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.024*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of non-advanced adenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.518\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e306 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87 (49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e89 (51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e194 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight and Left-\u003c/p\u003e \u003cp\u003e sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of advanced adenomas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (55%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5 (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight and Left-\u003c/p\u003e \u003cp\u003e sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of CRC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.355\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eData are median (IQR) and n (%). CRC\u0026thinsp;=\u0026thinsp;colorectal cancer. Advanced adenomas are defined as adenomas\u0026thinsp;\u0026gt;\u0026thinsp;10mm or with high-grade dysplasia. Non-advanced adenomas are adenomas\u0026thinsp;\u0026lt;\u0026thinsp;10mm and without high-grade dysplasia. Lesions are considered right-sided when located proximal of the splenic flexure. Lesions are considered left sided when located distal of the splenic flexure.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs shown in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the majority of CRCs identified during surveillance were classified as T1-stage tumours (52%) and none were classified as T4-stage tumours. The vast majority did not exhibit lymph node (85%) or distant metastases (97%). No significant differences in TNM stages were found among the various mutation groups. Individuals with LS who developed T1 CRC during life underwent subtotal colectomy in 32% of the cases, while partial colectomy and local treatment was performed in 32% and 36% (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Among those with T1 CRC detected during surveillance and in whom treatment deviated from the golden standard, in one of them a second carcinoma was detected. This individual had a T1 rectum carcinoma during his index coloscopy, which was treated by a low anterior resection. The second CRC was found in the ascending colon 12 years later. No metastases were detected and this CRC was adequately resected by a right hemicolectomy. During the follow up 13 years hereafter no third CRC has been detected in this individual.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTNM stadia of detected CRCs.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;78)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMLH1\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMSH2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMSH6\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePMS2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntramucosal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.283\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.122\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM0 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5 (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM1 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidences of performed treatments for T1 CRC removal in Lynch patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMLH1\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMSH2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMSH6\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePMS2\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.945\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubtotal \u003c/p\u003e \u003cp\u003e colectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial \u003c/p\u003e \u003cp\u003e colectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal \u003c/p\u003e \u003cp\u003e endoscopic\u003c/p\u003e \u003cp\u003e treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eData are n (%).CRC\u0026thinsp;=\u0026thinsp;colorectal cancer.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eNumerous studies demonstrated variations in CRC incidence among different LS-associated genes, but limited knowledge exists regarding customization of surveillance- and treatment strategies accordingly. Therefore, our analysis aimed to explore variations in occurrence and management of CRC and its precursor lesions during surveillance across different LS gPV groups. We showed, in accordance with current knowledge\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, that individuals with a gPV in \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e have higher life-time risks to develop CRC compared to \u003cem\u003eMSH6\u003c/em\u003e. In \u003cem\u003eMLH1\u003c/em\u003e the CRC risk is increased in men compared to women. Furthermore, we confirmed that in \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e CRC less often develops from visible precursor lesions, whereas in \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e significantly more visible precursor lesions are detected. Additionally we observed a considerable variation in performed treatments for T1 CRC.\u003c/p\u003e \u003cp\u003eThis study possesses several strengths. To our knowledge, it it represents one of the largest single center LS surveillance cohorts with complete surveillance data included. It reports CRC detection rates during surveillance across four different LS associated gPVs over a span of four decades. Additionally, apart from the CRC incidence, the incidence of precursor lesions, metachronous CRCs, TNM stadium from all CRCs and treatment strategies were analyzed. In contrast to prior research, this study only included individuals with confirmed LS-associated gPVs. Included individuals were under surveillance at a specialized LS centre staffed with experienced endoscopists. Lastly, to guarantee optimal quality all data were double checked, limiting the risk of information bias.\u003c/p\u003e \u003cp\u003eBig data databases, such as InSIGHT and PLDS, identify patterns and as such are useful as prediction models. They are determined by a tenfold of LS carriers compared to our single center cohort. Limitations of the PLDS database are first that the division between the four genes is skewed. As a result the presented \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e must be interpreted with caution. Also, the data from the large databases origin from many hospitals each including a considerably lower number of LS carriers compared to our cohort. InSIGHT and PLDS data are reported by the consulting specialists without double check. This might cause selection and reporting bias. Last precursor lesions and treatment variations are not reported in these databases.\u003c/p\u003e \u003cp\u003eThis study also exhibits several limitations. The retrospective design unavoidably resulted in missing data. However, despite the amount of missing data, significant differences or trends could be observed. Second, timing of precursor and carcinoma detection relied on the timing of colonoscopy procedures, possibly introducing information bias. In addition, improvements of imaging quality over time may have influenced lesion detection, potentially resulting in a higher number of lesions being detected in patients under surveillance nowadays compared to those monitored in the past. Though, in our cohort, as many as 69% of the individuals with LS have been under surveillance during the last 15 years, indicating that the majority of individuals with LS have been monitored with the most modern endoscopic equipment. Both timing of colonoscopy procedures as well as improvements in imaging quality could have possibly affected the overall detection rate. However, it is not expected these limitations would have directly influenced the proportion of detected lesions among mutation groups, as patients undergo similar surveillance protocols. Last a disadvantage of our single center design is that an extension of these findings to the wider group of individuals with LS worldwide might be under dispute.\u003c/p\u003e \u003cp\u003ePerforming biennial surveillance colonoscopies in individuals with LS has been shown to be essential, as it substantially improved the prognosis of individuals with LS caused by a gPV in one of the MMR genesdue to earlier detection of CRC and premalignant adenomas.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e However, effectiveness of the surveillance program heavily relies on adherence, and several studies already demonstrated adherence to timely colonoscopy surveillance in individuals with LS is not optimal.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In a study of Van Liere et al.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, it was shown that 57% of individuals with LS perceived the surveillance program as extremely burdensome, with even 10% considering quitting surveillance. Many individuals (60%) preferred a less invasive surveillance method. The current biennial surveillance program is thus clearly negatively influencing quality of life, especially if biennial checks may not even be necessary for certain LS associated gPV groups.\u003c/p\u003e \u003cp\u003eEarlier studies have already demonstrated variability in the lifetime risks of developing CRC among different individuals with LS, with carriers of a gPV in \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e being at highest hereditary CRC riske\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Consistently, in this study, we observed that \u003cem\u003eMLH1\u003c/em\u003e exhibited significantly higher CRC incidences at initial colonoscopy compared to other LS-associated gPV groups (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, with regard to detected lesions during surveillance colonoscopies, higher CRC incidences were observed in the \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e compared to the \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e. At the same time the observed non-advanced adenoma incidence was lower in \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2.\u003c/em\u003e This is in accordance with the most recent knowledge on CRC pathways in LS suggesting three different pathways.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e It is suggested that CRC development in \u003cem\u003eMLH1\u003c/em\u003e and \u003cem\u003eMSH2\u003c/em\u003e follows a more accelerated pathway with MMR deficient precursor foci in de colonic crypts.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e In \u003cem\u003eMLH1\u003c/em\u003e these foci might be located under the mucosal layer and as such might be easily overlooked.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe observed cumulative lifetime CRC incidence was higher in the \u003cem\u003eMLH1\u003c/em\u003e compared to \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e, as well as the cumulative lifetime CRC incidence of \u003cem\u003eMLH2\u003c/em\u003e compared to \u003cem\u003eMSH6\u003c/em\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These findings therefore suggest that, given the substantially lower lifetime risk of developing CRC and considering the negative impact of biennial surveillance on quality of life, surveillance intervals of \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e individuals could potentially be safely extended.\u003c/p\u003e \u003cp\u003eWe additionally investigated differences in TNM staging across the differentgPV groups and the corresponding performed treatments for early-stage CRC. As could be expected from the implementation of biennial surveillance\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, most CRCs detected during surveillance colonoscopies were T1 CRCs (52%) without the presence of lymph node- (85%) and distant (97%) metastasis (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). When examining the relatively small amount of patients with treated early-stage colorectal T1 CRCs (n\u0026thinsp;=\u0026thinsp;25), we observed considerable variation in performed treatments (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In 68% of the patients, physicians decided to deviate from the current guideline which recommends to perform subtotal colectomies for early stage CRC.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Less invasive local endoscopic treatment was performed more frequently than the golden standard (36% vs. 32%), clearly demonstrating preference and confidence in more local methods of treatment. Given the significant advancement in endoscopic techniques\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e and improved functional outcome after more local treatments\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, it is not surprising there has been growing preference for minimally invasive interventions in recent years. The current guideline for non-LS related colorectal T1 tumors\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e even already includes more tailored treatment recommendations, with endoscopic techniques considered superior to surgical resection in most cases. Specific histological risk factors have been identified for non-LS related colorectal T1 CRCs, including poor differentiation, lymph angioinvasion and high-grade tumor budding, which can predict the risk on metastases and recurrence in non-LS related colorectal T1 tumors.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e After endoscopic removal of non-LS related colorectal T1 CRCs, the presence or absence of these histological risk factors can subsequently assist in determining the need for additional surgical resection and/or in formulating the appropriate surveillance strategy.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Interestingly, only one of the LS patients treated for T1-stage CRC experienced a recurrence twelve years after a CRC was detected during the index colonoscopy, suggesting less invasive organ preserving treatment for LS-related colorectal T1 CRCs might also be a viable option. Nonetheless, evaluation of recurrence rates on the long-term is necessary given that local treatments were conducted more recently, leaving the possibility for recurrences to emerge.\u003c/p\u003e \u003cp\u003eIn our opinion, future studies should focus on distinguishing more personalized surveillance intervals for different LS associated gPV groups, possibly enabling extension of surveillance intervals for \u003cem\u003eMSH6\u003c/em\u003e and/or \u003cem\u003ePMS2\u003c/em\u003e given the smaller lifetime risks on developing CRC. Regarding treatment strategies for colorectal T1 CRCs, it is crucial to validate these findings in larger patients cohorts, with particular emphasis on monitoring the long-term outcomes of performed endoscopic treatments. In addition, it is interesting to investigate whether the current histological risk factors for non-LS related colorectal T1 CRCs also apply to LS-related colorectal T1 CRCs, and if so, whether these risk factors may vary across the different LS associated gPV groups.\u003c/p\u003e \u003cp\u003eIn conclusion, this large single center analysis showed a higher precursor lesion detection rate as well as a lower CRC incidences for individuals with LS caused by a gPV in \u003cem\u003eMSH6\u003c/em\u003e or \u003cem\u003ePMS2\u003c/em\u003e, suggesting the potential for extended surveillance intervals for these patients. Furthermore, consistent with biennial surveillance protocols, the majority of CRCs detected during surveillance were T1 CRCs without metastases. Regarding treatment of these T1 CRCs, considerable variation was observed with nearly equivalent recurrence rates, emphasizing the feasibility of less invasive endoscopic interventions for individuals with LS. To refine surveillance strategies, further investigation into extending surveillance intervals for individuals with LS caused by a gPV in \u003cem\u003eMSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e is needed. Additionally, assessing the long-term outcomes of diverse treatment modalities and identifying histological risk factors specific to LS-related colorectal T1 CRCs are essential steps towards optimizing treatment for LS individuals in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e \u003cp\u003eConflict of interest\u003c/p\u003e \u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e \u003cp\u003eContributions\u003c/p\u003e \u003cp\u003e \u003cb\u003eRomy N Kuipers \u0026amp; Marissa F Burggraaff\u003c/b\u003e (First Authors): Methodology; analysis, writing \u0026ndash; original draft; \u003cb\u003eMichiel HJ Maas\u003c/b\u003e (Author 2): Analysis, supervision, writing - review \u0026amp; editing; \u003cb\u003eDorien van der Biessen \u0026ndash; van Beek\u003c/b\u003e (Author 3): Gathering data, Writing \u0026ndash; Review \u0026amp; editing; \u003cb\u003eMari\u0026euml;tte C van Kouwen\u003c/b\u003e (Author 4): Writing - Review \u0026amp; editing; \u003cb\u003eTanya M Bisseling\u003c/b\u003e (senior author): Conceptualization; data curation; supervision; writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLynch HT, De la Chapelle A. 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Langers, Anna Lepist\u0026ouml;, Monika Morak, Gabriela M\u0026ouml;slein, P\u0026auml;ivi Peltom\u0026auml;ki, Kirsi Pylv\u0026auml;n\u0026auml;inen, Nils Rahner, Laura Renkonen-Sinisalo, Karsten Schulmann, Verena Steinke-Lange, Albrecht Stenzinger, Christian P. Strassburg, Paul C. van de Meeberg, Mariette van Kouwen, Monique van Leerdam, Deepak B. Vangala, Juda Vecht, Marie-Louise Verhulst, Magnus von Knebel Doeberitz, J\u0026uuml;rgen Weitz, Silke Zachariae, Markus Loeffler, Jukka-Pekka Mecklin, Matthias Kloor and Hans F. Vasen on behalf of the German HNPCC Consortium, the Dutch Lynch Syndrome Collaborative Group, and the Finnish Lynch Syndrome Registry. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. Gastroenterology 2020;158:1326\u0026ndash;1333\u003c/li\u003e\n\u003cli\u003eRudiman R. Advances in gastrointestinal surgical endoscopy. Annals of Medicine and Surgery 2021;72:103041.\u003c/li\u003e\n\u003cli\u003eRashid MU, Alomari M, Afraz S, Erim T. EMR and ESD: Indications, techniques and results. Surgical Oncology 2022;43:101742.\u003c/li\u003e\n\u003cli\u003eHaanstra JF, tot Nederveen WHdV, Gopie JP, Vecht J, Vanhoutvin SA, Cats A, van der Zaag-Loonen HJ, Langers AM, Bergmann JH, van de Meeberg PC. Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy. Diseases of the colon \u0026amp; rectum 2012;55(6):653-659.\u003c/li\u003e\n\u003cli\u003eFM S. Richtlijn Colorectaal Carcinoom (CRC). 2020.\u003c/li\u003e\n\u003cli\u003eFerlitsch M, Moss A, Hassan C, Bhandari P, Dumonceau J-M, Paspatis G, Jover R, Langner C, Bronzwaer M, Nalankilli K. Colorectal polypectomy and endoscopic mucosal resection (EMR): European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy 2017;49(03):270-297.\u003c/li\u003e\n\u003c/ol\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":"Lynch syndrome, adenomatous polyps, colorectal cancer, endoscopic surveillance, T1 colorectal cancer","lastPublishedDoi":"10.21203/rs.3.rs-6100008/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6100008/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNumerous studies have demonstrated variations in colorectal cancer (CRC) incidence among Lynch Syndrome (LS)-associated mutation carriers, but limited data are available regarding tailoring surveillance- and treatment strategies. Main goal of this study was to estimate whether personalized care could be offered based on respectively germline pathogenic variants (\u003cem\u003eMLH1\u003c/em\u003e, \u003cem\u003eMSH2\u003c/em\u003e, \u003cem\u003eMSH6\u003c/em\u003e or \u003cem\u003ePMS2\u003c/em\u003e). Additionally the outcome from patient shared care for early CRC was investigated.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSingle center retrospective cohort analysis including patients with one of 4 groups of LS-associated pathogenic variants (PV) (\u003cem\u003eMLH1\u003c/em\u003e, \u003cem\u003eMSH2\u003c/em\u003e, \u003cem\u003eMSH6\u003c/em\u003e or \u003cem\u003ePMS2\u003c/em\u003e) who underwent surveillance colonoscopies between January 1978 and February 2024. Analyses were performed to identify differences in precursor lesion- or CRC incidence and treatment among the PVs.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFrom a cohort of 621 LS individuals 496 (133 \u003cem\u003eMLH1\u003c/em\u003e, 107 \u003cem\u003eMSH2\u003c/em\u003e, 180 \u003cem\u003eMSH6\u003c/em\u003e and 76 \u003cem\u003ePMS2\u003c/em\u003e) could be included in this study. Analyses revealed that, despite adequate surveillance intervals and lower adenoma incidence, individuals with a gPV in \u003cem\u003eMLH1\u003c/em\u003e or \u003cem\u003eMSH2\u003c/em\u003e mutation carriers have higher CRC incidences compared to \u003cem\u003eMSH6\u003c/em\u003e or \u003cem\u003ePMS2.\u003c/em\u003e Most detected CRC lesions were early stage T1 CRCs. Treatment for T1 CRC varied considerably, in 68% of the cases deviating from the current golden standard subtotal colectomy, with nearly equivalent recurrence rates.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiscussion:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBased on higher precursor lesion detection and lower CRC incidences in LS individuals with a gPV in \u003cem\u003eMSH6\u003c/em\u003e or \u003cem\u003ePMS2\u003c/em\u003e under biannual endoscopic surveillance, this study supports the potential for extended surveillance intervals in the latter group. As treatment for the detected T1 CRCs varied considerably with nearly equivalent recurrence rates, it emphases the feasibility of less invasive interventions for LS individuals.\u003c/p\u003e","manuscriptTitle":"Endoscopic surveillance for colorectal cancer and its precursor lesions in Lynch syndrome; time for some policy shifts?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-10 09:53:49","doi":"10.21203/rs.3.rs-6100008/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-20T08:07:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-10T02:09:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62024236881311966168373598611354469","date":"2025-03-04T21:31:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-04T07:23:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-27T12:09:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-02-27T11:45:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hereditary Cancer in Clinical Practice","date":"2025-02-24T21:58:55+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":"7da6cdf9-2b27-4de2-a5c4-b10555f8e4c5","owner":[],"postedDate":"March 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-21T16:02:48+00:00","versionOfRecord":{"articleIdentity":"rs-6100008","link":"https://doi.org/10.1186/s13053-025-00312-z","journal":{"identity":"hereditary-cancer-in-clinical-practice","isVorOnly":false,"title":"Hereditary Cancer in Clinical Practice"},"publishedOn":"2025-04-16 15:57:17","publishedOnDateReadable":"April 16th, 2025"},"versionCreatedAt":"2025-03-10 09:53:49","video":"","vorDoi":"10.1186/s13053-025-00312-z","vorDoiUrl":"https://doi.org/10.1186/s13053-025-00312-z","workflowStages":[]},"version":"v1","identity":"rs-6100008","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6100008","identity":"rs-6100008","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}