Prognostic and Clinicopathological Implications of Mismatch-Repair Deficiency and MLH1 Promoter Methylation Status in Endometrial Carcinoma

Prognostic and Clinicopathological Implications of Mismatch-Repair Deficiency and MLH1 Promoter Methylation Status in Endometrial Carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic and Clinicopathological Implications of Mismatch-Repair Deficiency and MLH1 Promoter Methylation Status in Endometrial Carcinoma mayuko goda, Gou Yamamoto, Katsuya Iuchi, Koji Horie, Kiwamu Akagi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7235357/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Dec, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 4 You are reading this latest preprint version Abstract Objective: The prevalence of MSI-H and MLH1 promoter hypermethylation ( MLH1 -PHM) as well as Lynch syndrome in Japanese patients with endometrial cancer (EC) has not been fully revealed. There is also a recent report that the prognosis of MLH1 -PHM is worse than MLH1 non-PHM in EC; however, no large-scale studies have been conducted in Japan. We investigated the prevalence of MSI-H, MLH1 -PHM and Lynch syndrome in EC cases and characteristic and prognosis of them. Methods: The 677 patients who were pathologically diagnosed with EC at the Saitama Cancer Center Hospital between 2013 and 2023 were investigated in this study. The MSI and abnormal DNA methylation of the MLH1 promoter were tested in all cases. Patients with MSI-H EC or a family history provided informed consent and examined germline testing for Lynch syndrome. Results Among the 677 ECs, 170 (25.1%) were MSI-high (MSI-H), and 105 were involved MLH1 hypermethylation. Two of 13 Lynch syndrome cases had MLH1 -PHM in ECs. The MSI-H group had more G3 histology, but had a favorable prognosis with 5-year PFS and OS compared with the MSSgroup. The group with MLH1 -PHM have more patients with G1/2 histology and more advanced disease. There was no difference in prognosis between MLH1 -PHM and non-PHMgroups. Conclusion This study provides information on the prevalence of MIS-H and MLH1 -PHM in EC in Japan. Besides, the prognostic of MSI-H group is better than that in the MSSgroup, but no differences were found between the MLH1 -PHM and MLH1 non-PHM groups. endometrial cancer Lynch syndrome MSI-high MLH1 promoter methylation Figures Figure 1 Figure 2 Introduction Endometrial cancer (EC) has recently been molecularly classified [ 1 ], and the ProMisE classification was proposed [ 2 ]. Molecular classification is advocated for used as an indicator in EC risk assessment in European and other countries [ 3 ]. MSI-high (MSI-H) EC has an intermediate prognosis, as suggested by the ProMisE classification [ 4 ]. The MSI test for EC is now covered by public medical insurance in Japan as an ancillary test for predicting the effect of immune checkpoint inhibitors (ICIs). The WHO 2020 [ 5 ] and new FIGO2023 classifications of EC include molecular classification [ 6 ]; therefore, MSI testing has increased in Japan. Some patients with MSI-H EC have been diagnosed with Lynch syndrome (LS). Actually 2–5% of patients with EC carry a germline abnormality in the mismatch repair (MMR) gene [ 7 ][ 8 ]. Individuals with LS are at higher risk of developing malignancies such as endometrial, colorectal, and ovarian cancers [ 9 ]; therefore, correctly identifying Lynch syndrome is critically important. Recently, it was reported that the prognosis of MLH1 -PHM may be worse than that of MLH1 non-PHM in those with MSI-H EC [ 10 ] [ 11 ]. However, the number of MSI-H-deficient MMR (dMMR) cases was too small to draw conclusions [ 10 ] [ 12 ] [ 13 ], and few reports have been published on the background, pathology, and prognosis of MSI-H and MLH1 -PHM in Japanese clinical practice. We have conducted MSI and MLH1 -PHM analyses for 677 patients with EC since 2013, the largest number of cases in Asia. We investigated the proportions, clinical characteristics, and prognoses of patients with MSI-H and MSS/MSI-L EC in this study. Materials and Methods 1.Ethics and registration This study was conducted under the approval of the local ethics committee of the Saitama Cancer Center (No.476 and 729). Prior to the genetic testing for MMR gene variant, informed consent was obtained from each patient. 2.Patients The cohort was comprised of 677 patients with EC who underwent surgical hysterectomy at the Saitama Cancer Center from December 2013 to May 2023 and provided informed consent for this study. Characteristics and clinicopathologic data were collected from medical records. 3.MSI test DNA was extracted from the tumor and normal tissues using a QIAamp DNA mini kit (Quiagen GmbH, Hilden, Germany). The seven microsatellite loci, 5 Bethesda markers (BAT25, BAT26, D5S346, D17S250, and D2S123), NR21, and NR24 were amplified by PCR and subjected to fragment analysis using a capillary sequencer. Microsatellite instability at ≥ 2 loci was defined as MSI-high; instability at a single locus or no instability at any loci were defined MSI-low/MSS. 4. DNA methylation analysis Methylation status of MLH1 promoter was determined by Combined Bisulfite Restriction Analysis (COBRA) as previously reported [ 14 ]. 5 Classification and Detection of germline mutation Four MMR ( MLH1, MSH2, MSH6 and PMS2 ) and EPCAM genes were analyzed to detect germline pathogenic variants using DNA extracted from blood or normal tissue samples. 6.Statistical analysis Primary outcomes were characterization of MSI-H and MSI-L/MSS EC with respect to pathological features and prevalence of MIS-H in ECs. Secondary outcomes include overall survival (OS) and Progression-free survival (PFS). All data were analyzed using JMP version 11. Descriptive statistics were done using X² test for categorical variables and Student t test for continuous variables. For time to event analyses, the Kaplan Meier method was used. The PFS and OS associated with MSI-H and MSS tumors were compared using the log-rank test. Results Study population A total of 1014 patients with EC underwent surgical resection between 2013 and 2023. Of these, 677 patients were included in this study, and MSI and MLH1 -PHM analyses were performed (Fig. 1 ). The clinicopathological characteristics of the 677 patients are shown in Table 1 . The median age at EC diagnosis was 59 years (interquartile range Table 1 Clinicopathologic characteristics of ECs variables value All patients 677 Age at random assignment Median (IQR), y 59 (53–69) BMI Median (IQR) 23.4 (20.8–27.1) Para Median (IQR) 2 (1–2) Histological grade and type,No. (%) EEC grade 1 or 2 452 (66.8%) EEC grade 3 79 (11.7%) Mixed 23(3.4%) Clear cell 16 (2.4%) Serous 54 (8.0%) Carcinosarcoma 39 (5.8%) Other 14 (2.1%) FIGO 2008 stage, No. (%) Ⅰ・Ⅱ 526 (77.7%) Ⅲ・Ⅳ 151 (22.3%) EEC = endometrioid endometrial cancer, FIGO = International Federation of Gynecology and Obstetrics; IQR = interquartile range (IQR), 53–69), and the median BMI was 23.4 (IQR, 20.8–27.1). The results of histological analysis revealed that 531 and 145 patients had endometrioid and non-endometrioid carcinoma, respectively. The endometrioid carcinoma was graded G1 and G2 in 452 (66.8%) patients and G3 in 79 (11.7%) patients. The prevalence of serous carcinoma was the highest among those with non-endometrioid carcinomas. A total of 526 patients (77.7%) were classified as stages I and II, and 151 (22.3%) were classified in stages III and IV, according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging. These results are consistent with those reported by the Japanese Society of Gynecologic Oncology (14) The study flowchart is shown in Fig. 1 . Among the 677 patients with EC, 169 (24.9%) were classified as MSI-H. MLH1 -PHM was detected in 105 tumors (62.1% MSI-H EC)., MLH1 -PHM analysis was also conducted in the MSS/MSI-L group, and approximately 1% (5/508) were classified as MLH1 -PHM. Germline testing for LS was conducted in 102, resulting in 14 positive cases: two and one were MLH1 -PHM and MSS cases, respectively. Details of the patients with LS are listed in Table 2 . MSH6 was the most frequently identified causative gene of LS in EC, accounting for 50% (7/14) of the cases. Table 2 Characteristics of patient with LS No. Age Histo type FIGO Stage MSI status Coding sequence change Amino acid change MLH1 promoter methylation Personal cancer history Family cancer history 1 43 G3 ⅢC1 MSS MLH1: c.1103C > A p.Ser368* + CC:45 years TC:49 years - 2 77 Mixed ⅠA MSI-H MSH6: c.3261dup p.Phe1088Leufs*5 - - Father: GC Paternal grandmother: GC Maternal uncle: GC 3 40 G1 ⅠA double MSI-H MSH6: c.3202C > T p.Arg1068* - - Mother: OC 4 53 Mixed ⅠA double MSI-H MSH6: c.3747delC p.His1250Ilefs*3 - Mother: EC Maternal cousin: CC 5 53 G1 ⅢC1 MSI-H MSH2: c.561_562 ins SVA p.Tyr165Leufs*20 - Father: GC Paternal aunt: EC Paternal cousin: EC 6 59 G1 ⅠA MSI-H MSH6: c.3142C > T p.Gln1048* - Mother: BC Father: RC Paternal grandmother: EC 7 50 Mixed ⅢC1 MSI-H MSH6: c.1444C > T p.Arg482*) - Mother: EC CC 8 57 G1 ⅠA double MSI-H MSH6: c.443del p.Leu148fs ་ - 9 54 G1 ⅠA MSI-H MSH6: c.4001 + 1delG p.Ala1268Glyfs*6 - Mother: CC Father: TG 10 56 G1 ⅠA MSI-H MSH2: c.1277–5615_1387-5086del p.Lys427Glyfs*4 - CC:42 years Mother: OC Father: RC Sister: EC Brother: CC 11 51 G2 Ⅱ MSI-H PMS2: c.353 + 419_803 + 134del p.Asp119_Tyr268del - Father: GC CC 12 40 G1 ⅠA MSI-H MLH1: c1721T > C p.Leu574Pro - ML:35years Aunt:CU 13 41 G3 Ⅱ MSI-H MSH2: c.942 + 3A > T p.Val265_Gln314del - - Father: CC Paternal aunt: EC PC Paternal aunt: GC 14 52 G3 Ⅱ MSI-H PMS2: c.353 + 419_803 + 134del p.Asp119_Tyr268del - - Maternal aunt: CC CC, colon cancer; TC,tyroid cancer; GC, gastric cancer; OC, ovarian cancer; EC, endometrial cancer; BC, breast cancer; RC, rectal cancer; TG, tongue cancer; ML, malignant lymphoma; CU, cancer unknown in detail; PC, pancreatic cancer Clinicopathologic features of MSI-H and MSS/MSI-L EC The clinicopathological characteristics of the patients with MSI-H or MSS/MSI-L EC are shown in Table 3 . Age and FIGO stage did not substantially differ between the groups. The prevalence of the EC G3 histological type was higher in MSI-H than in MSI-L/MSS. The frequency of postoperative chemotherapy (paclitaxel and carboplatin were used for the high-risk group after surgery at our hospital) did not significantly differ between the groups. Table 3 Clinicopathologic characteristics of patients with MSI-H and MSS/MSI-L ECs variables MSI-H (169) MSI-L/MSS (508) P-value Total, No. (%) 169 (24.9) 508 (62.1) Age at random assignment Median (IQR), y 57 (54–69) 60 (53–69) 0.3 FIGO 2008 stage, No. (%) Ⅰ・Ⅱ 130 (76.9%) 396 (78%) 0.78 Ⅲ・Ⅳ 39 (23.1%) 112 (22%) Histological grade and type, No.(%) EEC grade 1 or 2 116 (68.6%) 336 (66.1%) < .0001 EEC grade 3 33 (19.5%) 46 (9.0%) Mixed 9 (5.3%) 30 (5.9%) Clear cell 2 (1.2%) 14 (2.8%) Serous 4 (2.4%) 50 (9.8%) Carcinosarcoma 0 (0%) 23 (4.5%) Other 5 (3.0%) 9 (1.8%) Received adjuvant treatment, No.(%)(Paclitaxel + Carboplatin) 64 (37.9%) 156 (30.7%) 0.08 EEC = endometrioid endometrial cancer, FIGO = International Federation of Gynecology and Obstetrics; IQR = interquartile range Clinicopathologic features of MSI-H EC with MLH1 -PHM or MLH1 -non-PHM We examined the clinicopathological characteristics of MSI-H EC differed between MLH1 -PHM and non-PHM (Table 4 ). The prevalence of stage III/IV (FIGO 2008) tended to be higher (27.6%) in MLH1 -PHM MSI-H EC than in MLH1 non-PHM MSI-H EC (15.6%, p = 0.072); the prevalence of EEC grade 1 or 2 was also higher in the former (74.3 vs. 59.4, p = 0.0332). Table 4 Clinicopathologic characteristics of MSI-H ECs with MLH1 -PHM and non-PHM variables MLH1 methylated MSI-H non methylated P-value Total, No. (%) 105 64 Age at random assignment Median (IQR), y 58 (54–58) 57 (53–69) 0.72 FIGO 2008 stage, No. (%) Ⅰ・Ⅱ 76 (72.4) 54 (84.4) 0.072 Ⅲ・Ⅳ 29 (27.6) 10 (15.6) Histological grade and type, No.(%) EEC grade 1 or 2 78 (74.3) 38 (59.4) 0.0332 EEC grade 3 19 (18.1) 14 (21.9) Mixed 3 (2.9) 6 (9.4) Clear cell 1 (1.0) 1 (1.6) Serous 0 (0) 4 (6.2) Others 4 (3.8) 1 (1.6) EEC = endometrioid endometrial cancer, FIGO = International Federation of Gynecology and Obstetrics; IQR = interquartile range Survival The estimated 5-year PFS for patients with MSI-H EC with MLH1 -PHM and non-PHM as well as those with MSS/MSI-L EC was 92.2% 94.5%, and 81.9%, respectively (Fig. 2 a). PFS was significantly longer in the MSI-H group than in the MSS/MSI-L group (log-rank test, p = 0.013). The prognosis did not differ between MLH1 hypermethylation and non-hypermethylation in the overall group. The estimated OS at 5 years was 91.2% for MLH1 -PHM, 98.4% for MLH1 non-PHM, and 85.6% for MSS/MSI-L (Fig. 2 b). The OS was also higher in the MSI-H group (log-rank test; p = 0.0233). We assessed the OS and PFS of each EC group according to the FIGO staging system. The estimated 5-year PFS for stage I/II was 97.2%, 97.1%, and 89.3% (p = 0.0243; Fig. 2 c), and the estimated 5-year OS was 96.0%, 100%, and 95.7%(p = 0.27) for MLH1 -PHM, MLH1 non-PHM, and MSS/MSI-L, respectively (Fig. 2 d). The 5-year PFS rates were 79.9%, 80%, and 54.1% (p = 0.0179) (Fig. 2 e) and the 5-year OS rates were 81.5%, 90%, and 56.1% (p = 0.0252) for MLH1 -PHM, MLH1 non-PHM, and MSS/MSI-L for those at stage III/IV, respectively (Fig. 2 f). The FIGO-stage-specific results also showed a trend toward a better prognosis for those with MSI-H. However, the prognosis did not notably differ between the MLH1 -PHM and non-PHM MSI-H EC groups. Discussion MSI testing and MMR immunohistochemistry for EC in Japan is currently covered by health insurance. However, treatment options for advanced or recurrent endometrial cancer have increased, making treatment decisions more complex. The frequency of MSI testing has been increasing owing to the need for molecularly classifying EC, as proposed by FIGO 2023, and the introduction of new ICIs. The MSI-H proportion in those with EC was 25%, the prevalence of LS in those with MSI-H EC was 16%, and the frequency of LS in all patients with EC was estimated as 3.8% in this study. The prevalences of MSI-H/dMMR and LS in EC were previously reported to be 25–31% and 1.3–3.7%, respectively [ 15 ] [ 16 ] [ 17 ]. The frequency of MSI-H/dMMR EC is higher than that of other cancers [ 18 ] [ 19 ]. The percentage of MLH1 -PHM in those with MSI-H/dMMR EC is approximately 70% [ 10 ] [ 17 ] [ 20 ]. Yamamoto et al. reported that among 68 people with uterine cancers with dMMR in Japan, the loss of MLH1 and PMS2 expressions was found in 53, and 51 (75%) patients showed hypermethylation [ 17 ]. Kaneko et al. reported that the percentage of MLH1 -PHM in those with dMMR EC was 38.9% [ 22 ], indicating discrepancies in reports from Japan. Our study included the largest number of cases of EC reported in Asia. The percentage of MLH1 -PHM in these patients with EC was 62.1%, which is comparable to that reported in large studies in other countries [ 21 ]. We analyzed MLH1 -PHM for all patients and found that approximately 1% of those with MSS EC had MLH1 -PHM. We also found that 2 of the 14 (14%) people with LS developed EC with MLH1 -PHM, indicating that LS should not be excluded even in those with MLH1 -PHM EC. The proportion of the endometrioid cancer G3 histological type, which has a poor prognosis, was markedly higher in patients with MSI-H than in those with MSS/MSI-L EC. These results are similar to those of previous studies [ 8 ] [ 15 ]. The histological type appears to be uncorrelated with the clinical prognosis in patients with MSI-H EC according to the patient backgrounds and the results of this prognostic study. Those with MLH1 -PHM tended to be in G1/2 and more advanced stages compared with non-PHM cases in the evaluation of MSI-H EC, which is similar to the findings of Cathaline et al., who studied 410 patients with MSI-H/dMMR [ 10 ]. Other researchers have also found that the EC stages of those with MLH1 -PHM is more likely to be advanced [ 11 ] [ 21 ]. We also found that patients with MSI-H EC tended to have a longer PFS and higher OS than those with MSS/MSI-L EC. None of the patients with EC diagnosed with LS relapsed or died from EC during the follow-up period. The prognosis for LS is generally good [ 10 ] [ 15 ]. Patients with dMMR EC had higher OS and longer PFS than those with proficient MMR (pMMR) EC in a retrospective study in Japan [ 22 ]. Black et al. found that those with MSI-H EC had significantly longer disease-free survival, despite the proportion of advanced-stage cases being higher than that of those with MSS EC [ 23 ]. The results of these studies are similar to ours. Although POLE and p53 were not examined in our study, the overlap between POLE and MSI-H/dMMR is approximately 0.9% [ 24 ]. POLE has little impact on the prognosis of MSI-H/dMMR EC, according to these results. These results collectively indicate that the prognosis for patients with MSI-H/dMMR EC is good in patients of EC that underwent surgery. We also investigated the prognosis of patients with MLH1 -PHM and non-PHM; the two groups did not notably differ in 5-year OS or PFS (Fig. 2 a,b). Cathalijne et al. divided patients with EC into an LS dMMR group, a methylated dMMR group, and an ‘other’ dMMR group. They examined the 5-year RFS; they reported that the RFS of those in the methylated dMMR group was 78.6%, the lowest among the groups [ 13 ]. In addition, McMeekin et al. reported that dMMR caused by MLH1 methylation had a relatively worse prognosis than dMMR caused by probable MMR mutations or pMMR in large clinical cohorts [ 25 ]. Although we found no difference in the prognosis between patients with and without methylation, other studies suggested that MLH1 hypermethylation was associated with a worse prognosis [ 25 ]. As such, further studies are required to investigate this issue. The effect of ICIs on MLH1 hypermethylation EC has been reported. Sloan et al. found that the expression level of PD-L1 in MLH1 -PHM EC was lower than that in non-PHM EC [ 26 ]. Bellone et al. similarly found that the response rates to ICIs were 100% and 44% for patients with the MMR somatic mutation and MLH1 hypermethylation, respectively [ 27 ], and Michael concluded MLH1 hypermethylation significantly decreased survival. These patients responded differently to ICIs than patients with MLH1 mutations [ 28 ]. In addition, ICIs were administered in two cases of recurrent endometrial cancer with MLH1 hypermethylation; however, both cases showed progressive disease as the best response after 3 and 9 months of treatment, respectively. The use of ICIs for treating EC is rapidly expanding; however, the efficacy of ICIs in treating those with MSI-H/dMMR EC may be affected by the MLH1 promoter methylation status. As such, drugs must be carefully selected: ICI + chemotherapy for MLH1 hypermethylation and ICI only for MLH1 non-hypermethylation. Therefore, therapeutic strategies including ICIs should continue to be verified in future studies. This study is not without limitations. First, this study was conducted at a single institution, so the results may not be generalizable. The diagnosis of LS was not definitive in all cases because the patients were asked to decide whether to undergo diagnostic testing for LS. However, the selection of surgical and adjuvant therapies was consistent because this study was conducted at a single institution, which is a strength when considering prognosis. Second, we examined the 5-year PFS and OS when considering the prognosis of those with non-LS MSI-H with MLH1 -PHM; only one case of recurrence was noted in each group. Therefore, the number of patients was small, and the prognosis could not be fully examined. However, the MLH1 methylation status was tested in all cases, addressing a gap in knowledge, as few researchers have examined the background and prognosis of cases from Japan with and without MLH1 -PHM. Therefore, the data from this study can be used to investigate the effects of MLH1 methylation in EC. LS and MSI-H have good prognoses, and performing MSI and MLH1 hypermethylation testing will enable clinicians to provide more accurate prognosis estimates. A difference in the efficacy of ICIs between those with MLH1 -PHM and non-PHM, as well as for MSI-H, may arise as the use of ICI expands. Further studies are needed to confirm this hypothesis. Declarations Acknowledgments This research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant JP 18kk0205004, JSPS KAKENHI under grant number JP18K07339, and the National Cancer Center Research and Development Fund Number 31-A-2. Conflicts of interest The authors have no relevant financial or non-financial interests to disclose. References Cancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497(7447):67-73. Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, et al (2015) A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 113(2):299-310. Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al (2021) ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 31(1):12-39. Talhouk A, McConechy MK, Leung S, Yang W, Lum A, Senz J, et al (2017) Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer 123(5):802-13. IARC. WHO Classification of Tumors. Female genital tumours.2020. Berek JS, Matias-Guiu X, Creutzberg C, Fotopoulou C, Gaffney D, Kehoe S, et al (2023) FIGO staging of endometrial cancer. J Gynecol Oncol 34(5):e85. Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, et al (2006) Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 66(15):7810-7. Kahn RM, Gordhandas S, Maddy BP, Baltich Nelson B, Askin G, Christos PJ, et al (2019) Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population? Cancer 125(18):3172-83. Leclerc J, Vermaut C, Buisine MP (2021) Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors. Cancers (Basel) 13(3). Post CCB, Stelloo E, Smit V, Ruano D, Tops CM, Vermij L, et al (2021) Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer. J Natl Cancer Inst 113(9):1212-20. Cosgrove CM, Cohn DE, Hampel H, Frankel WL, Jones D, McElroy JP, et al (2017) Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival. Gynecol Oncol 146(3):588-95. Loukovaara M, Pasanen A, Butzow R (2021) Mismatch repair protein and MLH1 methylation status as predictors of response to adjuvant therapy in endometrial cancer. Cancer Med 10(3):1034-42. Kim J, Kong JK, Yang W, Cho H, Chay DB, Lee BH, et al (2018) DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer. Cancers (Basel) 10(9). Nagasaka T, Koi M, Kloor M, Gebert J, Vilkin A, Nishida N, et al (2008) Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology 134(7):1950-60, 60 e1. Gynecology JSoOa. Patient Anuual Peport for 2021: Japan Society of Obstetrics and Gynecology; 2021 [Available from: https://fa.kyorin.co.jp/jsog/readPDF.php?file=75/12/075121643.pdf. Kato MK, Fujii E, Asami Y, Momozawa Y, Hiranuma K, Komatsu M, et al (2024) Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer. Cancer Sci 115(5):1646-55. Takahashi K, Sato N, Sugawara T, Kato A, Sato T, Shimizu D, et al (2017) Clinical characteristics of Lynch-like cases collaterally classified by Lynch syndrome identification strategy using universal screening in endometrial cancer. Gynecol Oncol 147(2):388-95. Yamamoto A, Yamaguchi T, Suzuki O, Ito T, Chika N, Kamae N, et al (2021) Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population. Jpn J Clin Oncol 51(1):60-9. Akagi K, Oki E, Taniguchi H, Nakatani K, Aoki D, Kuwata T, et al (2021) The real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer Sci Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, et al (2019) Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol 37(4):286-95. Pasanen A, Loukovaara M, Butzow R (2020) Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma. Mod Pathol 33(7):1443-52. Kaneko E, Sato N, Sugawara T, Noto A, Takahashi K, Makino K, et al (2021) MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas. J Gynecol Oncol 32(6):e79. Kato M, Takano M, Miyamoto M, Sasaki N, Goto T, Tsuda H, et al (2015) DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers. J Gynecol Oncol 26(1):40-5. Black D, Soslow RA, Levine DA, Tornos C, Chen SC, Hummer AJ, et al (2006) Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. J Clin Oncol 24(11):1745-53. Leon-Castillo A, Britton H, McConechy MK, McAlpine JN, Nout R, Kommoss S, et al (2020) Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 250(3):323-35. McMeekin DS, Tritchler DL, Cohn DE, Mutch DG, Lankes HA, Geller MA, et al (2016) Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol 34(25):3062-8. Sloan EA, Ring KL, Willis BC, Modesitt SC, Mills AM (2017) PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinomas, Including Lynch Syndrome-associated and MLH1 Promoter Hypermethylated Tumors. Am J Surg Pathol 41(3):326-33. Bellone S, Roque DM, Siegel ER, Buza N, Hui P, Bonazzoli E, et al (2021) A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics (NCT02899793). Ann Oncol 32(8):1045-6. Toboni MD, Wu S, Farrell A, Xiu J, Ribeiro JR, Oberley MJ, et al (2023) Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation. Gynecol Oncol 177:132-41. Cite Share Download PDF Status: Published Journal Publication published 17 Dec, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Reviewers agreed at journal 12 Aug, 2025 Reviewers invited by journal 12 Aug, 2025 Editor assigned by journal 11 Aug, 2025 First submitted to journal 06 Aug, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-7235357","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":499151474,"identity":"ed4f34a8-09a3-466f-a4a2-d8c880426484","order_by":0,"name":"mayuko goda","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIiWNgGAWjYPCCBAZ+EMUDYiHAAfxaJBtI1mJwAFMLdqDbfsZMuqAmTd74+OnEB28Y6vL4JZIfMPMw2MkzMJ7Fao3ZmRwz6RnHcgy3ncndbDiH4XCx5Iw0A6CWZMMGhnNYrTQ7ANTCw1bBuO0G7zZpHoYDiRtuJ5j/5mFgBio/Y4BVy/k3QC3/Kuw3z+DdDlRZB9SS/gFoSz1uLTeAtvC25SRukODdBlTJDNSSA3LYYTxanhVb8/alJc8A+kVyjsHhxJnz3xQwzjE4btiGyy/nkzfe5vmWbNvffnbjhzcVdYn9PMc3MLypqJbnl8AeYgwMHMi2GyAx2CTOYNfBwP4AhwQDfw8umVEwCkbBKBhZAAAcvV9ezWmWmQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8727-8958","institution":"Saitama Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"mayuko","middleName":"","lastName":"goda","suffix":""},{"id":499151475,"identity":"84fcf355-e11d-488a-8c66-c522d0ffd832","order_by":1,"name":"Gou Yamamoto","email":"","orcid":"","institution":"Saitama Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Gou","middleName":"","lastName":"Yamamoto","suffix":""},{"id":499151476,"identity":"1a567a36-9d32-4de0-9fc1-c55f3c93774b","order_by":2,"name":"Katsuya Iuchi","email":"","orcid":"","institution":"Saitama Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Katsuya","middleName":"","lastName":"Iuchi","suffix":""},{"id":499151477,"identity":"2d8c2942-2c9a-45cc-8b7b-44e3b42917f8","order_by":3,"name":"Koji Horie","email":"","orcid":"","institution":"Saitama Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Horie","suffix":""},{"id":499151478,"identity":"b82f715a-5d14-44eb-9e01-1d84d769ef4a","order_by":4,"name":"Kiwamu Akagi","email":"","orcid":"","institution":"Saitama Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Kiwamu","middleName":"","lastName":"Akagi","suffix":""}],"badges":[],"createdAt":"2025-07-28 15:15:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7235357/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7235357/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02913-z","type":"published","date":"2025-12-17T15:58:33+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89454435,"identity":"fd0db107-dfb1-440f-8a5a-3e56ad0e94ec","added_by":"auto","created_at":"2025-08-20 06:46:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77513,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart for identification of patients with \u003cem\u003eMLH1\u003c/em\u003e-methylated and MSI-H, patients with LS. (MSI: microsatellite instability)\u003c/p\u003e","description":"","filename":"renamedaa1f8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7235357/v1/f1d92c7ceb9200ea8f204551.jpg"},{"id":89455741,"identity":"c087d43b-8605-4211-8a37-1b8d5253288d","added_by":"auto","created_at":"2025-08-20 06:54:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":294063,"visible":true,"origin":"","legend":"\u003cp\u003ePrognosis of MSS/MSI-L and MSI-H EM carcinoma cases with \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHM\u003c/p\u003e\n\u003cp\u003ea) The estimated PFS at 5 years was 92.2% for MLH1 methylated, 94.5% for MSI-H non methylated and 81.7% for MSI-L/MSS. (p=0.013)\u003c/p\u003e\n\u003cp\u003eb) The estimated OS at 5 years was 91.2% for MLH1 methylated, 98.4% for MSI-H non methylated and 85.6% for MSI-L/MSS. (p=0.0233)\u003c/p\u003e\n\u003cp\u003ec) The estimated PFS at 5 years was 97.2% for MLH1 methylated, 97.1% for MSI-H non methylated and 89.3% for MSI-L/MSS in FIGO Stage I/II. (p=0.0243)\u003c/p\u003e\n\u003cp\u003ed) The estimated OS at 5 years was 96.0% for MLH1 methylated, 100% for MSI-H non methylated and 95.7% for MSI-L/MSS in FIGO Stage I/II. (p=0.27)\u003c/p\u003e\n\u003cp\u003ee) The estimated PFS at 5 years was 79.9% for MLH1 methylated, 80.0% for MSI-H non methylated and 54.1% for MSI-L/MSS in FIGO Stage III/IV. (p=0.0179)\u003c/p\u003e\n\u003cp\u003ef) The estimated OS at 5 years was 81.5% for MLH1 methylated, 90% for MSI-H non methylated and 56.1% for MSI-L/MSS in FIGO Stage III/IV. (p=0.0252)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7235357/v1/c36b1f3438cb272109932515.png"},{"id":98814033,"identity":"f8f80505-ef4a-4ebb-917f-29d3c10caab4","added_by":"auto","created_at":"2025-12-22 16:09:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1294921,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7235357/v1/e847903e-6a72-447f-9220-f88f61043622.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003ePrognostic and Clinicopathological Implications of Mismatch-Repair Deficiency and MLH1 Promoter Methylation Status in Endometrial Carcinoma\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometrial cancer (EC) has recently been molecularly classified [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], and the ProMisE classification was proposed [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Molecular classification is advocated for used as an indicator in EC risk assessment in European and other countries [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. MSI-high (MSI-H) EC has an intermediate prognosis, as suggested by the ProMisE classification [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The MSI test for EC is now covered by public medical insurance in Japan as an ancillary test for predicting the effect of immune checkpoint inhibitors (ICIs). The WHO 2020 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and new FIGO2023 classifications of EC include molecular classification [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]; therefore, MSI testing has increased in Japan. Some patients with MSI-H EC have been diagnosed with Lynch syndrome (LS). Actually 2\u0026ndash;5% of patients with EC carry a germline abnormality in the mismatch repair (MMR) gene [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e][\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Individuals with LS are at higher risk of developing malignancies such as endometrial, colorectal, and ovarian cancers [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]; therefore, correctly identifying Lynch syndrome is critically important. Recently, it was reported that the prognosis of \u003cem\u003eMLH1\u003c/em\u003e-PHM may be worse than that of \u003cem\u003eMLH1\u003c/em\u003e non-PHM in those with MSI-H EC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, the number of MSI-H-deficient MMR (dMMR) cases was too small to draw conclusions [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and few reports have been published on the background, pathology, and prognosis of MSI-H and \u003cem\u003eMLH1\u003c/em\u003e-PHM in Japanese clinical practice.\u003c/p\u003e\u003cp\u003eWe have conducted MSI and \u003cem\u003eMLH1\u003c/em\u003e-PHM analyses for 677 patients with EC since 2013, the largest number of cases in Asia. We investigated the proportions, clinical characteristics, and prognoses of patients with MSI-H and MSS/MSI-L EC in this study.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cb\u003e1.Ethics and registration\u003c/b\u003e\u003c/p\u003e\u003cp\u003e This study was conducted under the approval of the local ethics committee of the Saitama Cancer Center (No.476 and 729). Prior to the genetic testing for MMR gene variant, informed consent was obtained from each patient.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.Patients\u003c/b\u003e\u003c/p\u003e\u003cp\u003e The cohort was comprised of 677 patients with EC who underwent surgical hysterectomy at the Saitama Cancer Center from December 2013 to May 2023 and provided informed consent for this study. Characteristics and clinicopathologic data were collected from medical records.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3.MSI test\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDNA was extracted from the tumor and normal tissues using a QIAamp DNA mini kit (Quiagen GmbH, Hilden, Germany). The seven microsatellite loci, 5 Bethesda markers\u003c/p\u003e\u003cp\u003e(BAT25, BAT26, D5S346, D17S250, and D2S123), NR21, and NR24 were amplified by PCR and subjected to fragment analysis using a capillary sequencer. Microsatellite instability at \u0026ge;\u0026thinsp;2 loci was defined as MSI-high; instability at a single locus or no instability at any loci were defined MSI-low/MSS.\u003c/p\u003e\u003cp\u003e\u003cb\u003e4. DNA methylation analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMethylation status of \u003cem\u003eMLH1\u003c/em\u003e promoter was determined by Combined Bisulfite Restriction Analysis (COBRA) as previously reported [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003e5 Classification and Detection of germline mutation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFour MMR (\u003cem\u003eMLH1, MSH2, MSH6\u003c/em\u003e and \u003cem\u003ePMS2\u003c/em\u003e) and \u003cem\u003eEPCAM\u003c/em\u003e genes were analyzed to detect germline pathogenic variants using DNA extracted from blood or normal tissue samples.\u003c/p\u003e\u003cp\u003e\u003cb\u003e6.Statistical analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePrimary outcomes were characterization of MSI-H and MSI-L/MSS EC with respect to pathological features and prevalence of MIS-H in ECs. Secondary outcomes include overall survival (OS) and Progression-free survival (PFS). All data were analyzed using JMP version 11. Descriptive statistics were done using X\u0026sup2; test for categorical variables and Student t test for continuous variables. For time to event analyses, the Kaplan Meier method was used. The PFS and OS associated with MSI-H and MSS tumors were compared using the log-rank test.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eA total of 1014 patients with EC underwent surgical resection between 2013 and 2023. Of these, 677 patients were included in this study, and MSI and \u003cem\u003eMLH1\u003c/em\u003e-PHM analyses were performed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The clinicopathological characteristics of the 677 patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age at EC diagnosis was 59 years (interquartile range\u003c/p\u003e\u003cp\u003e\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\u003e\u003cb\u003eClinicopathologic characteristics of ECs\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003evariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003evalue\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e677\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at random assignment\u003c/p\u003e\u003cp\u003e Median (IQR), y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59 (53\u0026ndash;69)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI Median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23.4 (20.8\u0026ndash;27.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePara Median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistological grade and type,No. (%)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEEC grade 1 or 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e452 (66.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEEC grade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e79 (11.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23(3.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClear cell\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54 (8.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCarcinosarcoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39 (5.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (2.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO 2008 stage, No. (%)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅠ・Ⅱ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e526 (77.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅢ・Ⅳ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e151 (22.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eEEC\u0026thinsp;=\u0026thinsp;endometrioid endometrial cancer, FIGO\u0026thinsp;=\u0026thinsp;International Federation of Gynecology and Obstetrics; IQR\u0026thinsp;=\u0026thinsp;interquartile range\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e(IQR), 53\u0026ndash;69), and the median BMI was 23.4 (IQR, 20.8\u0026ndash;27.1). The results of histological analysis revealed that 531 and 145 patients had endometrioid and non-endometrioid carcinoma, respectively. The endometrioid carcinoma was graded G1 and G2 in 452 (66.8%) patients and G3 in 79 (11.7%) patients. The prevalence of serous carcinoma was the highest among those with non-endometrioid carcinomas. A total of 526 patients (77.7%) were classified as stages I and II, and 151 (22.3%) were classified in stages III and IV, according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging. These results are consistent with those reported by the Japanese Society of Gynecologic Oncology (14)\u003c/p\u003e\u003cp\u003eThe study flowchart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among the 677 patients with EC, 169 (24.9%) were classified as MSI-H. \u003cem\u003eMLH1\u003c/em\u003e-PHM was detected in 105 tumors (62.1% MSI-H EC)., \u003cem\u003eMLH1\u003c/em\u003e-PHM analysis was also conducted in the MSS/MSI-L group, and approximately 1% (5/508) were classified as \u003cem\u003eMLH1\u003c/em\u003e-PHM. Germline testing for LS was conducted in 102, resulting in 14 positive cases: two and one were \u003cem\u003eMLH1\u003c/em\u003e-PHM and MSS cases, respectively. Details of the patients with LS are listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. \u003cem\u003eMSH6\u003c/em\u003e was the most frequently identified causative gene of LS in EC, accounting for 50% (7/14) of the cases.\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\u003eCharacteristics of patient with LS\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" 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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHisto\u003c/p\u003e\u003cp\u003etype\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFIGO\u003c/p\u003e\u003cp\u003eStage\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI status\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCoding sequence change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAmino acid change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMLH1 promoter methylation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePersonal cancer history\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eFamily cancer history\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅢC1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMLH1: c.1103C\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Ser368*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e+\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCC:45 years TC:49 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH6: c.3261dup\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Phe1088Leufs*5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eFather: GC Paternal grandmother: GC Maternal uncle: GC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA double\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH6: c.3202C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Arg1068*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMother: OC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA double\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH6: c.3747delC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.His1250Ilefs*3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMother: EC Maternal cousin: CC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅢC1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH2: c.561_562 ins SVA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Tyr165Leufs*20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eFather: GC Paternal aunt: EC Paternal cousin: EC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH6: c.3142C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Gln1048*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMother: BC Father: RC\u003c/p\u003e\u003cp\u003ePaternal grandmother: EC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅢC1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH6: c.1444C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Arg482*)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMother: EC CC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA double\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH6: c.443del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Leu148fs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e་\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH6: c.4001\u0026thinsp;+\u0026thinsp;1delG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Ala1268Glyfs*6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMother: CC\u003c/p\u003e\u003cp\u003eFather: TG\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH2: c.1277\u0026ndash;5615_1387-5086del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Lys427Glyfs*4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCC:42 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMother: OC Father: RC Sister: EC\u003c/p\u003e\u003cp\u003eBrother: CC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅡ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePMS2: c.353\u0026thinsp;+\u0026thinsp;419_803\u0026thinsp;+\u0026thinsp;134del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Asp119_Tyr268del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eFather: GC CC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅠA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMLH1: c1721T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Leu574Pro\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eML:35years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eAunt:CU\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅡ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMSH2: c.942\u0026thinsp;+\u0026thinsp;3A\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Val265_Gln314del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eFather: CC Paternal aunt: EC PC Paternal aunt: GC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eⅡ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMSI-H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePMS2: c.353\u0026thinsp;+\u0026thinsp;419_803\u0026thinsp;+\u0026thinsp;134del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep.Asp119_Tyr268del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMaternal aunt: CC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eCC, colon cancer; TC,tyroid cancer; GC, gastric cancer; OC, ovarian cancer; EC, endometrial cancer; BC, breast cancer; RC, rectal cancer; TG, tongue cancer; ML, malignant lymphoma; CU, cancer unknown in detail; PC, pancreatic cancer\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinicopathologic features of MSI-H and MSS/MSI-L EC\u003c/h3\u003e\n\u003cp\u003eThe clinicopathological characteristics of the patients with MSI-H or MSS/MSI-L EC are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Age and FIGO stage did not substantially differ between the groups. The prevalence of the EC G3 histological type was higher in MSI-H than in MSI-L/MSS. The frequency of postoperative chemotherapy (paclitaxel and carboplatin were used for the high-risk group after surgery at our hospital) did not significantly differ between the groups.\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\u003e\u003cb\u003eClinicopathologic characteristics of patients with MSI-H and MSS/MSI-L ECs\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003evariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMSI-H (169)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMSI-L/MSS (508)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\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\u003eTotal, No. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e169 (24.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e508 (62.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at random assignment\u003c/p\u003e\u003cp\u003e Median (IQR), y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57 (54\u0026ndash;69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60 (53\u0026ndash;69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO 2008 stage, No. (%)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅠ・Ⅱ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e130 (76.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e396 (78%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅢ・Ⅳ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (23.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e112 (22%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistological grade and type, No.(%)\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEEC grade 1 or 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e116 (68.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e336 (66.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEEC grade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e33 (19.5%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46 (9.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (5.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 (5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClear cell\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (2.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50 (9.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCarcinosarcoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (4.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (3.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (1.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReceived adjuvant treatment, No.(%)(Paclitaxel\u0026thinsp;+\u0026thinsp;Carboplatin)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64 (37.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e156 (30.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eEEC\u0026thinsp;=\u0026thinsp;endometrioid endometrial cancer, FIGO\u0026thinsp;=\u0026thinsp;International Federation of Gynecology and Obstetrics; IQR\u0026thinsp;=\u0026thinsp;interquartile range\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinicopathologic features of MSI-H EC with\u003c/b\u003e \u003cb\u003eMLH1\u003c/b\u003e\u003cb\u003e-PHM or\u003c/b\u003e \u003cb\u003eMLH1\u003c/b\u003e\u003cb\u003e-non-PHM\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe examined the clinicopathological characteristics of MSI-H EC differed between \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHM (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The prevalence of stage III/IV (FIGO 2008) tended to be higher (27.6%) in \u003cem\u003eMLH1\u003c/em\u003e-PHM MSI-H EC than in \u003cem\u003eMLH1\u003c/em\u003e non-PHM MSI-H EC (15.6%, p\u0026thinsp;=\u0026thinsp;0.072); the prevalence of EEC grade 1 or 2 was also higher in the former (74.3 vs. 59.4, p\u0026thinsp;=\u0026thinsp;0.0332).\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\u003eClinicopathologic characteristics of MSI-H ECs with \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHM\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=\"char\" char=\".\" 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=\"char\" char=\".\" 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\u003cp\u003evariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003eMLH1\u003c/em\u003e methylated\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eMSI-H non methylated\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\u003eTotal, No. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e105\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e64\u003c/p\u003e\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\u003eAge at random assignment\u003c/p\u003e\u003cp\u003e Median (IQR), y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(54\u0026ndash;58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(53\u0026ndash;69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO 2008 stage, No. (%)\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\u003eⅠ・Ⅱ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(72.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(84.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.072\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅢ・Ⅳ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(27.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(15.6)\u003c/p\u003e\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\u003eHistological grade and type, No.(%)\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\u003eEEC grade 1 or 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(74.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(59.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.0332\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEEC grade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(18.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(21.9)\u003c/p\u003e\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\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(9.4)\u003c/p\u003e\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\u003eClear cell\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(1.6)\u003c/p\u003e\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\u003eSerous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(6.2)\u003c/p\u003e\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\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eEEC\u0026thinsp;=\u0026thinsp;endometrioid endometrial cancer, FIGO\u0026thinsp;=\u0026thinsp;International Federation of Gynecology and Obstetrics; IQR\u0026thinsp;=\u0026thinsp;interquartile range\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eSurvival\u003c/h3\u003e\n\u003cp\u003eThe estimated 5-year PFS for patients with MSI-H EC with \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHM as well as those with MSS/MSI-L EC was 92.2% 94.5%, and 81.9%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). PFS was significantly longer in the MSI-H group than in the MSS/MSI-L group (log-rank test, p\u0026thinsp;=\u0026thinsp;0.013). The prognosis did not differ between \u003cem\u003eMLH1\u003c/em\u003e hypermethylation and non-hypermethylation in the overall group. The estimated OS at 5 years was 91.2% for \u003cem\u003eMLH1\u003c/em\u003e-PHM, 98.4% for \u003cem\u003eMLH1\u003c/em\u003e non-PHM, and 85.6% for MSS/MSI-L (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). The OS was also higher in the MSI-H group (log-rank test; p\u0026thinsp;=\u0026thinsp;0.0233). We assessed the OS and PFS of each EC group according to the FIGO staging system. The estimated 5-year PFS for stage I/II was 97.2%, 97.1%, and 89.3% (p\u0026thinsp;=\u0026thinsp;0.0243; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec), and the estimated 5-year OS was 96.0%, 100%, and 95.7%(p\u0026thinsp;=\u0026thinsp;0.27) for \u003cem\u003eMLH1\u003c/em\u003e-PHM, \u003cem\u003eMLH1\u003c/em\u003e non-PHM, and MSS/MSI-L, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). The 5-year PFS rates were 79.9%, 80%, and 54.1% (p\u0026thinsp;=\u0026thinsp;0.0179) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee) and the 5-year OS rates were 81.5%, 90%, and 56.1% (p\u0026thinsp;=\u0026thinsp;0.0252) for \u003cem\u003eMLH1\u003c/em\u003e-PHM, \u003cem\u003eMLH1\u003c/em\u003e non-PHM, and MSS/MSI-L for those at stage III/IV, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe FIGO-stage-specific results also showed a trend toward a better prognosis for those with MSI-H. However, the prognosis did not notably differ between the \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHM MSI-H EC groups.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMSI testing and MMR immunohistochemistry for EC in Japan is currently covered by health insurance. However, treatment options for advanced or recurrent endometrial cancer have increased, making treatment decisions more complex. The frequency of MSI testing has been increasing owing to the need for molecularly classifying EC, as proposed by FIGO 2023, and the introduction of new ICIs.\u003c/p\u003e\u003cp\u003eThe MSI-H proportion in those with EC was 25%, the prevalence of LS in those with MSI-H EC was 16%, and the frequency of LS in all patients with EC was estimated as 3.8% in this study. The prevalences of MSI-H/dMMR and LS in EC were previously reported to be 25\u0026ndash;31% and 1.3\u0026ndash;3.7%, respectively [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The frequency of MSI-H/dMMR EC is higher than that of other cancers [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The percentage of \u003cem\u003eMLH1\u003c/em\u003e-PHM in those with MSI-H/dMMR EC is approximately 70% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Yamamoto et al. reported that among 68 people with uterine cancers with dMMR in Japan, the loss of MLH1 and PMS2 expressions was found in 53, and 51 (75%) patients showed hypermethylation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Kaneko et al. reported that the percentage of \u003cem\u003eMLH1\u003c/em\u003e-PHM in those with dMMR EC was 38.9% [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], indicating discrepancies in reports from Japan.\u003c/p\u003e\u003cp\u003eOur study included the largest number of cases of EC reported in Asia. The percentage of \u003cem\u003eMLH1\u003c/em\u003e-PHM in these patients with EC was 62.1%, which is comparable to that reported in large studies in other countries [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We analyzed \u003cem\u003eMLH1\u003c/em\u003e-PHM for all patients and found that approximately 1% of those with MSS EC had \u003cem\u003eMLH1\u003c/em\u003e-PHM. We also found that 2 of the 14 (14%) people with LS developed EC with \u003cem\u003eMLH1\u003c/em\u003e-PHM, indicating that LS should not be excluded even in those with \u003cem\u003eMLH1\u003c/em\u003e-PHM EC.\u003c/p\u003e\u003cp\u003eThe proportion of the endometrioid cancer G3 histological type, which has a poor prognosis, was markedly higher in patients with MSI-H than in those with MSS/MSI-L EC. These results are similar to those of previous studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The histological type appears to be uncorrelated with the clinical prognosis in patients with MSI-H EC according to the patient backgrounds and the results of this prognostic study.\u003c/p\u003e\u003cp\u003eThose with \u003cem\u003eMLH1\u003c/em\u003e-PHM tended to be in G1/2 and more advanced stages compared with non-PHM cases in the evaluation of MSI-H EC, which is similar to the findings of Cathaline et al., who studied 410 patients with MSI-H/dMMR [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Other researchers have also found that the EC stages of those with \u003cem\u003eMLH1\u003c/em\u003e-PHM is more likely to be advanced [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe also found that patients with MSI-H EC tended to have a longer PFS and higher OS than those with MSS/MSI-L EC. None of the patients with EC diagnosed with LS relapsed or died from EC during the follow-up period. The prognosis for LS is generally good [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePatients with dMMR EC had higher OS and longer PFS than those with proficient MMR (pMMR) EC in a retrospective study in Japan [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Black et al. found that those with MSI-H EC had significantly longer disease-free survival, despite the proportion of advanced-stage cases being higher than that of those with MSS EC [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The results of these studies are similar to ours. Although \u003cem\u003ePOLE\u003c/em\u003e and p53 were not examined in our study, the overlap between \u003cem\u003ePOLE\u003c/em\u003e and MSI-H/dMMR is approximately 0.9% [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. \u003cem\u003ePOLE\u003c/em\u003e has little impact on the prognosis of MSI-H/dMMR EC, according to these results. These results collectively indicate that the prognosis for patients with MSI-H/dMMR EC is good in patients of EC that underwent surgery.\u003c/p\u003e\u003cp\u003eWe also investigated the prognosis of patients with \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHM; the two groups did not notably differ in 5-year OS or PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea,b). Cathalijne et al. divided patients with EC into an LS dMMR group, a methylated dMMR group, and an \u0026lsquo;other\u0026rsquo; dMMR group. They examined the 5-year RFS; they reported that the RFS of those in the methylated dMMR group was 78.6%, the lowest among the groups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition, McMeekin et al. reported that dMMR caused by \u003cem\u003eMLH1\u003c/em\u003e methylation had a relatively worse prognosis than dMMR caused by probable MMR mutations or pMMR in large clinical cohorts [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Although we found no difference in the prognosis between patients with and without methylation, other studies suggested that \u003cem\u003eMLH1\u003c/em\u003e hypermethylation was associated with a worse prognosis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. As such, further studies are required to investigate this issue.\u003c/p\u003e\u003cp\u003eThe effect of ICIs on \u003cem\u003eMLH1\u003c/em\u003e hypermethylation EC has been reported. Sloan et al. found that the expression level of PD-L1 in \u003cem\u003eMLH1\u003c/em\u003e-PHM EC was lower than that in non-PHM EC [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Bellone et al. similarly found that the response rates to ICIs were 100% and 44% for patients with the MMR somatic mutation and \u003cem\u003eMLH1\u003c/em\u003e hypermethylation, respectively [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and Michael concluded \u003cem\u003eMLH1\u003c/em\u003e hypermethylation significantly decreased survival. These patients responded differently to ICIs than patients with \u003cem\u003eMLH1\u003c/em\u003e mutations [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In addition, ICIs were administered in two cases of recurrent endometrial cancer with \u003cem\u003eMLH1\u003c/em\u003e hypermethylation; however, both cases showed progressive disease as the best response after 3 and 9 months of treatment, respectively. The use of ICIs for treating EC is rapidly expanding; however, the efficacy of ICIs in treating those with MSI-H/dMMR EC may be affected by the \u003cem\u003eMLH1\u003c/em\u003e promoter methylation status. As such, drugs must be carefully selected: ICI\u0026thinsp;+\u0026thinsp;chemotherapy for MLH1 hypermethylation and ICI only for \u003cem\u003eMLH1\u003c/em\u003e non-hypermethylation. Therefore, therapeutic strategies including ICIs should continue to be verified in future studies.\u003c/p\u003e\u003cp\u003eThis study is not without limitations. First, this study was conducted at a single institution, so the results may not be generalizable. The diagnosis of LS was not definitive in all cases because the patients were asked to decide whether to undergo diagnostic testing for LS. However, the selection of surgical and adjuvant therapies was consistent because this study was conducted at a single institution, which is a strength when considering prognosis. Second, we examined the 5-year PFS and OS when considering the prognosis of those with non-LS MSI-H with \u003cem\u003eMLH1\u003c/em\u003e-PHM; only one case of recurrence was noted in each group. Therefore, the number of patients was small, and the prognosis could not be fully examined. However, the \u003cem\u003eMLH1\u003c/em\u003e methylation status was tested in all cases, addressing a gap in knowledge, as few researchers have examined the background and prognosis of cases from Japan with and without \u003cem\u003eMLH1\u003c/em\u003e-PHM. Therefore, the data from this study can be used to investigate the effects of \u003cem\u003eMLH1\u003c/em\u003e methylation in EC.\u003c/p\u003e\u003cp\u003eLS and MSI-H have good prognoses, and performing MSI and \u003cem\u003eMLH1\u003c/em\u003e hypermethylation testing will enable clinicians to provide more accurate prognosis estimates. A difference in the efficacy of ICIs between those with \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHM, as well as for MSI-H, may arise as the use of ICI expands. Further studies are needed to confirm this hypothesis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant JP 18kk0205004, JSPS KAKENHI under grant number JP18K07339, and the National Cancer Center Research and Development Fund Number 31-A-2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497(7447):67-73.\u003c/li\u003e\n\u003cli\u003eTalhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, et al (2015) A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 113(2):299-310.\u003c/li\u003e\n\u003cli\u003eConcin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al (2021) ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 31(1):12-39.\u003c/li\u003e\n\u003cli\u003eTalhouk A, McConechy MK, Leung S, Yang W, Lum A, Senz J, et al (2017) Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer 123(5):802-13.\u003c/li\u003e\n\u003cli\u003eIARC. WHO Classification of Tumors. Female genital tumours.2020.\u003c/li\u003e\n\u003cli\u003eBerek JS, Matias-Guiu X, Creutzberg C, Fotopoulou C, Gaffney D, Kehoe S, et al (2023) FIGO staging of endometrial cancer. J Gynecol Oncol 34(5):e85.\u003c/li\u003e\n\u003cli\u003eHampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, et al (2006) Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 66(15):7810-7.\u003c/li\u003e\n\u003cli\u003eKahn RM, Gordhandas S, Maddy BP, Baltich Nelson B, Askin G, Christos PJ, et al (2019) Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population? Cancer 125(18):3172-83.\u003c/li\u003e\n\u003cli\u003eLeclerc J, Vermaut C, Buisine MP (2021) Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors. Cancers (Basel) 13(3).\u003c/li\u003e\n\u003cli\u003ePost CCB, Stelloo E, Smit V, Ruano D, Tops CM, Vermij L, et al (2021) Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer. J Natl Cancer Inst 113(9):1212-20.\u003c/li\u003e\n\u003cli\u003eCosgrove CM, Cohn DE, Hampel H, Frankel WL, Jones D, McElroy JP, et al (2017) Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival. Gynecol Oncol 146(3):588-95.\u003c/li\u003e\n\u003cli\u003eLoukovaara M, Pasanen A, Butzow R (2021) Mismatch repair protein and MLH1 methylation status as predictors of response to adjuvant therapy in endometrial cancer. Cancer Med 10(3):1034-42.\u003c/li\u003e\n\u003cli\u003eKim J, Kong JK, Yang W, Cho H, Chay DB, Lee BH, et al (2018) DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer. Cancers (Basel) 10(9).\u003c/li\u003e\n\u003cli\u003eNagasaka T, Koi M, Kloor M, Gebert J, Vilkin A, Nishida N, et al (2008) Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology 134(7):1950-60, 60 e1.\u003c/li\u003e\n\u003cli\u003eGynecology JSoOa. Patient Anuual Peport for 2021: Japan Society of Obstetrics and Gynecology; 2021 [Available from: https://fa.kyorin.co.jp/jsog/readPDF.php?file=75/12/075121643.pdf.\u003c/li\u003e\n\u003cli\u003eKato MK, Fujii E, Asami Y, Momozawa Y, Hiranuma K, Komatsu M, et al (2024) Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer. Cancer Sci 115(5):1646-55.\u003c/li\u003e\n\u003cli\u003eTakahashi K, Sato N, Sugawara T, Kato A, Sato T, Shimizu D, et al (2017) Clinical characteristics of Lynch-like cases collaterally classified by Lynch syndrome identification strategy using universal screening in endometrial cancer. Gynecol Oncol 147(2):388-95.\u003c/li\u003e\n\u003cli\u003eYamamoto A, Yamaguchi T, Suzuki O, Ito T, Chika N, Kamae N, et al (2021) Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population. Jpn J Clin Oncol 51(1):60-9.\u003c/li\u003e\n\u003cli\u003eAkagi K, Oki E, Taniguchi H, Nakatani K, Aoki D, Kuwata T, et al (2021) The real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer Sci \u003c/li\u003e\n\u003cli\u003eLatham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, et al (2019) Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol 37(4):286-95.\u003c/li\u003e\n\u003cli\u003ePasanen A, Loukovaara M, Butzow R (2020) Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma. Mod Pathol 33(7):1443-52.\u003c/li\u003e\n\u003cli\u003eKaneko E, Sato N, Sugawara T, Noto A, Takahashi K, Makino K, et al (2021) MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas. J Gynecol Oncol 32(6):e79.\u003c/li\u003e\n\u003cli\u003eKato M, Takano M, Miyamoto M, Sasaki N, Goto T, Tsuda H, et al (2015) DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers. J Gynecol Oncol 26(1):40-5.\u003c/li\u003e\n\u003cli\u003eBlack D, Soslow RA, Levine DA, Tornos C, Chen SC, Hummer AJ, et al (2006) Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. J Clin Oncol 24(11):1745-53.\u003c/li\u003e\n\u003cli\u003eLeon-Castillo A, Britton H, McConechy MK, McAlpine JN, Nout R, Kommoss S, et al (2020) Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 250(3):323-35.\u003c/li\u003e\n\u003cli\u003eMcMeekin DS, Tritchler DL, Cohn DE, Mutch DG, Lankes HA, Geller MA, et al (2016) Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol 34(25):3062-8.\u003c/li\u003e\n\u003cli\u003eSloan EA, Ring KL, Willis BC, Modesitt SC, Mills AM (2017) PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinomas, Including Lynch Syndrome-associated and MLH1 Promoter Hypermethylated Tumors. Am J Surg Pathol 41(3):326-33.\u003c/li\u003e\n\u003cli\u003eBellone S, Roque DM, Siegel ER, Buza N, Hui P, Bonazzoli E, et al (2021) A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics (NCT02899793). Ann Oncol 32(8):1045-6.\u003c/li\u003e\n\u003cli\u003eToboni MD, Wu S, Farrell A, Xiu J, Ribeiro JR, Oberley MJ, et al (2023) Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 \u0026quot;Lynch-like\u0026quot; mismatch repair gene mutation. Gynecol Oncol 177:132-41.\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"endometrial cancer, Lynch syndrome, MSI-high, MLH1 promoter methylation","lastPublishedDoi":"10.21203/rs.3.rs-7235357/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7235357/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe prevalence of MSI-H and \u003cem\u003eMLH1\u003c/em\u003e promoter hypermethylation (\u003cem\u003eMLH1\u003c/em\u003e-PHM) as well as Lynch syndrome in Japanese patients with endometrial cancer (EC) has not been fully revealed. There is also a recent report that the prognosis of \u003cem\u003eMLH1\u003c/em\u003e-PHM is worse than \u003cem\u003eMLH1\u003c/em\u003e non-PHM in EC; however, no large-scale studies have been conducted in Japan. We investigated the prevalence of MSI-H, \u003cem\u003eMLH1\u003c/em\u003e-PHM and Lynch syndrome in EC cases and characteristic and prognosis of them.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe 677 patients who were pathologically diagnosed with EC at the Saitama Cancer Center Hospital between 2013 and 2023 were investigated in this study. The MSI and abnormal DNA methylation of the \u003cem\u003eMLH1\u003c/em\u003epromoter were tested in all cases. Patients with MSI-H EC or a family history provided informed consent and examined germline testing for Lynch syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 677 ECs, 170 (25.1%) were MSI-high (MSI-H), and 105 were involved \u003cem\u003eMLH1 \u003c/em\u003ehypermethylation. Two of 13 Lynch syndrome cases had \u003cem\u003eMLH1\u003c/em\u003e-PHM in ECs. The MSI-H group had more G3 histology, but had a favorable prognosis with 5-year PFS and OS compared with the MSSgroup. The group with \u003cem\u003eMLH1\u003c/em\u003e-PHM have more patients with G1/2 histology and more advanced disease. There was no difference in prognosis between \u003cem\u003eMLH1\u003c/em\u003e-PHM and non-PHMgroups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study provides information on the prevalence of MIS-H and \u003cem\u003eMLH1\u003c/em\u003e-PHM in EC in Japan. Besides, the prognostic of MSI-H group is better than that in the MSSgroup, but no differences were found between the \u003cem\u003eMLH1\u003c/em\u003e-PHM and \u003cem\u003eMLH1 \u003c/em\u003enon-PHM groups.\u003c/p\u003e","manuscriptTitle":"Prognostic and Clinicopathological Implications of Mismatch-Repair Deficiency and MLH1 Promoter Methylation Status in Endometrial Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-20 06:46:42","doi":"10.21203/rs.3.rs-7235357/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-08-12T06:58:40+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-12T05:23:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-11T14:01:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-08-06T18:52:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6c6c1e9c-6f3d-4331-930f-6372987b9ea2","owner":[],"postedDate":"August 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-22T16:03:17+00:00","versionOfRecord":{"articleIdentity":"rs-7235357","link":"https://doi.org/10.1007/s10147-025-02913-z","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-12-17 15:58:33","publishedOnDateReadable":"December 17th, 2025"},"versionCreatedAt":"2025-08-20 06:46:42","video":"","vorDoi":"10.1007/s10147-025-02913-z","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02913-z","workflowStages":[]},"version":"v1","identity":"rs-7235357","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7235357","identity":"rs-7235357","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}