Prevalence and clinicopathologic features of mismatch repair–deficient endometrial cancer in Japanese patients younger than 50 years: a single-center prospective observational study

Prevalence and clinicopathologic features of mismatch repair–deficient endometrial cancer in Japanese patients younger than 50 years: a single-center prospective observational study | 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 Prevalence and clinicopathologic features of mismatch repair–deficient endometrial cancer in Japanese patients younger than 50 years: a single-center prospective observational study Hidetaka Nomura, Akiko Abe, Atsushi Fusegi, Shogo Yamaguchi, Tsubasa Kon, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7776818/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Apr, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Universal tumor testing is increasingly recommended for Lynch syndrome (LS). However, data involving younger Japanese patients are still limited. This study aimed to prospectively evaluate the prevalence and clinicopathologic profile of DNA mismatch repair (MMR)–deficient (dMMR) endometrial cancers (EC) in patients aged under 50 years, and characterize immunohistochemical (IHC) loss patterns and genetic testing results. Methods Consecutive patients with EC aged under 50 years were prospectively enrolled at a single Japanese institution. Diagnostic specimens underwent MMR IHC ( MLH1, MSH2, MSH6 , and PMS2 ). Clinicopathologic variables were compared between proficient MMR (pMMR) and dMMR. Results Among 85 patients, 20 (23.5%) had dMMR. Grades differed when dichotomized as G1 versus G2–G3 ( p < 0.01). FIGO stage distribution also varied between groups ( p = 0.021); stage I was 53/65 (81.5%) in pMMR and 11/20 (55.0%) in dMMR ( p = 0.035). Among dMMR tumors, IHC patterns were loss of MLH1/PMS2 ( n = 10), loss of MSH2/MSH6 ( n = 5), and isolated loss of MSH6 ( n = 5). Of the 8 (40.0%) patients with dMMR who underwent germline testing, 5 had LS ( MLH1/PMS2 loss: 1/3; MSH2/MSH6 loss: 3/3; MSH6 isolated loss: 1/2). The overall dMMR prevalence in this young cohort was comparable to that in all-age series from multiple regions. Conclusions In this prospective Japanese cohort, approximately one in four patients with EC had dMMR, with clinicopathologic features skewing toward a higher grade. Notably, many dMMR tumors were grade 2–3, thereby not eligible for fertility-sparing treatment. dMMR endometrial cancer IHC Lynch syndrome universal screening Introduction Lynch syndrome (LS) is an autosomal dominant hereditary disorder caused by germline pathogenic variants in mismatch repair (MMR) genes such as MLH1, MSH2, MSH6 , and PMS2 . Carriers of germline pathogenic variants in these causative genes have a high lifetime risk of developing multiple malignancies, including colorectal cancer, endometrial cancer (EC), ovarian cancer, gastric cancer, and urothelial cancer [ 1 ]. Universal screening of MMR proteins via immunohistochemistry (IHC) has been widely adopted in Western countries and is recommended by several guidelines, given its cost-effectiveness and diagnostic yield [ 2 – 7 ]. Colonoscopic surveillance has significantly reduced the incidence and mortality of colorectal cancer in patients with LS, highlighting the importance of early identification [ 8 ]. Universal screening for MMR deficiency (dMMR) in EC is also rapidly gaining global acceptance; however, it has primarily been evaluated in unselected, mixed-age cohorts. Currently, age-restricted analyses are limited, and the detection rate of LS in younger patients remains unclear. This evidence gap is especially pronounced in Asian populations, underscoring the need for prospective data focused on younger women. Identifying LS during primary diagnosis is critical for both affected individuals and at-risk family members to early detect cancer, provide risk-reducing interventions, and improve the prognosis. In LS, EC is often the first diagnosed “sentinel” cancer; hence, its proper evaluation plays a central role in hereditary cancer diagnosis. Although dMMR has been reported to be prevalent in EC, many previous studies have focused on advanced or recurrent cases or on general populations without age restriction. To date, prospective data focusing exclusively on women aged under 50 years, including those from Asia, remain limited. In this study, we aimed to prospectively evaluate the prevalence and clinical characteristics of dMMR among Japanese patients aged 50 years and below who were diagnosed with EC. Patients and Methods This study obtained approval from the Institutional Review Board of our institution (IRB No. : 2021-GB-076) and conformed to the principles of the Declaration of Helsinki. MMR IHC for study purposes was performed only in patients who provided written informed consent. IHC categories were as follows: loss of MLH1/PMS2 , loss of MSH2/MSH6 , isolated loss of MSH6 , and isolated loss of PMS2 . When dMMR was identified, patients were referred to the Department of Clinical Genetics, where they received genetic counseling. Based on this, the option of germline testing for Lynch syndrome (LS) was discussed. This prospective observational study enrolled patients aged under 50 years who were diagnosed with EC at our institution between November 2020 and December 2024. MMR proteins ( MLH1, MSH2, MSH6 , and PMS2 ) from surgical specimens obtained at primary surgery were analyzed by IHC. IHC was also performed on biopsy specimens obtained during diagnosis from patients managed with fertility-sparing therapy without hysterectomy. The following clinical data were collected: age at diagnosis, histological grade (G1 to G3, carcinosarcoma, etc.), family history (the presence and familial aggregation of LS-related cancers), and genetic testing results. LS-related cancers included colorectal cancer (including rectal cancer), brain tumors, biliary tract cancer, gastric cancer, pancreatic cancer, small intestinal cancer, ovarian cancer, and cancers of the renal pelvis or ureter. Family history was classified into three categories: no LS-related cancer, LS-related cancer in a first-degree relative, and LS-related cancer only in second-degree relatives. Regarding MMR status, dMMR was considered only when loss of nuclear expression on IHC was unequivocal and conformed to predefined patterns. Conversely, equivocal/patchy/weak staining, subclonal loss of uncertain significance, or internal-control failure were not counted as dMMR, thereby categorized as indeterminate. Then, dMMR cases were subclassified as MLH1/PMS2 loss, MSH2/MSH6 loss, MSH6 isolated loss, or PMS2 isolated loss. The causative genes were estimated using descriptive and comparative statistics. To assess the association between MMR status and clinicopathological features, we conducted chi-squared test. Statistical analyses were performed using the chi-squared test to evaluate associations between MMR status and categorical clinicopathological variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated where appropriate. A p-value of < 0.05 was considered statistically significant. All analyses were conducted using R version 3.6.1. Results Of the 85 patients included in this study, 20 (23.5%) had dMMR according to IHC. Table 1 summarizes the baseline patient characteristics by MMR status. The frequency of pregnancy (G ≥ 1: 40.0% vs. 30.8%; p = 0.587) and delivery (P ≥ 1: 20.0% vs. 27.7%; p = 0.572), as well as concurrent ovarian cancer (30.0% vs. 20.0%; p = 0.528), was similar between the pMMR and dMMR groups. FIGO stage distribution differed between such groups ( p = 0.021). Stage I comprised the vast majority (53/65, 81.5%) in the pMMR group but was significantly less frequent in the dMMR group (11/20, 55.0%; p = 0.035). Accordingly, stages II–IV were more common in dMMR (9/20, 45.0%) than in pMMR (12/65, 18.5%). Moreover, postoperative chemotherapy was more common in dMMR (13/20 [65.0%]) than in pMMR (16/65 [24.6%]; p = 0.0023; OR, 5.69; 95% CI, 1.93–16.72). At our institution, adjuvant chemotherapy is generally administered to patients with EC with an intermediate or higher risk of recurrence, providing clinical context for the observed pattern. Table 1 Baseline patient characteristics by MMR status pMMR (n = 65) dMMR (n = 20) p-value Notes Age, years (median [IQR]) 43 (39–46) 44 (41–48) 0.457 gravida ≥ 1 20 (30.8%) 8 (40%) 0.587 paras ≥ 1 18 (27.7%) 4 (20%) 0.572 Family history category 0.038 Chi-square, Cat0/1/2 overall 0 39 (60%) 7 (35%) 1 16 (24.6%) 11 (55%) Cat1 vs Cat0: p = 0.023 Fisher (dMMR rate 11/27 vs 7/46) 2 10 (15.4%) 2 (10%) Concurrent ovarian cancer 13 (20%) 6 (30%) 0.528 Histology 0.001 Fisher, G1 vs others Grade 1 48 (73.8%) 6 (30.0%) Grade 2 8 (12.3%) 8 (40.0%) Grade 3 6 (9.2%) 6 (30.0%) other 3 (4.6%) 0 (0.0%) FIGO stage 0.035 Fisher, I vs II–IV I 53 (81.5%) 11 (55%) II 4 (6.2%) 6 (30%) III 5 (7.7%) 1 (5%) IV 3 (4,6%) 2 (10%) adjuvant chemotherapy 16 (24.6%) 13 (65%) 0.002 Table 2 summarizes the IHC patterns of the 20 dMMR cases, of which 10 (50%) had MLH1/PMS2 loss, 5 (25%) had MSH2/MSH6 loss, and 5 (25%) had MSH6 isolated loss. None had PMS2 isolated loss. Regarding histological characteristics, grade 1 endometrioid adenocarcinoma (73.8%) was found in most of those in the pMMR group but only 30% in the dMMR group. Conversely, grade 2 (40%) and grade 3 (30%) tumors were more common among dMMR cases. When grades were dichotomized as G1 versus G2–G3, the distribution differed significantly between such groups (pMMR: 48/17 vs. dMMR: 6/14; p < 0.01). With regard to the association with LS-related family history, dMMR was most prevalent in patients with first-degree relatives affected by LS (category 1) (40.7%), followed by those with only second-degree relatives affected (category 2) (16.7%) and those without an LS-related family history (category 0) (14.9%). Their difference was statistically significant ( p = 0.025). Of the 10 patients with MLH1/PMS2 loss, 3 underwent germline testing, and among them, only 1 was diagnosed with LS (33.3%). Additionally, 3 of the 5 patients with MSH2/MSH6 loss underwent testing, and all of them were found to have LS (100%). Table 2 dMMR prevalence and IHC loss patterns across representative universal-screening cohorts Country Cohort / Study N (population) Age dMMR prevalence MLH1 + PMS2 MSH2 and MSH6 MSH2-only MSH6-only PMS2-only Japan Hospital-based (JJCO 2021) 395 (all-comers) Median 59 17.2% (68/395) 77.9% (53/68) 13.2% (9/68) 2.9% (2/68) 4.4% (3/68) 1.5% (1/68) Canada MUSE (Curr Oncol 2021) 261 (all-comers) < 70 vs ≥ 70 reported 26.4% (69/261) 82.6% (57/69) 8.7% (6/69) MSH2 and/or MSH6 NA NA 4.3% (3/69) Sweden National program (Hered Cancer Clin Pract 2024) 221 (all-comers) Not restricted 24% (54/221) 83.3% (45/54) 16.7% (9/54) MSH2 and/or MSH6 NA NA 0% Iran Single-center (Caspian J Intern Med 2022) 100 (all-comers) Mean 56.6 23% (23/100) 17.4% 17.4% (MSH2 loss) NA 13.0% (reported as PMS2/MSH2) NA USA Multi-institutional (Gynecol Oncol 2020) 1,018 (all-comers) Not restricted 28.4% (289/1018) NA NA NA NA NA Japan Current study (≤ 50 y) 85 (≤ 50) ≤ 50 23.5% (20/85) 50.0% (10/20) 25.0% (5/20) 0% 25.0% (5/20) 0% NA: not applicable Table 3 Germline testing by immunohistochemistry staining loss pattern among dMMR patients IHC loss pattern n Tested positive MLH1 + PMS2 10 3 (30%) 1 (33.3%) MSH2 + MSH6 5 3 (60%) 3 (100%) MSH6-only 5 2 (40%) 1 (50%) Total 20 8 (40%) 5 (62.5%) Discussion The prevalence of dMMR in our age-restricted cohort (20/85 (23.5%) was unexpectedly comparable to rates reported in unselected, all-age series across regions (Table 2 ). Reported rates included 17.2% in a Japanese hospital-based cohort by Yamamoto et al. [ 9 ], 26.4% in a Canadian universal-screening program described by Lawrence et al. [ 10 ], 24% in a Swedish national implementation study by Andersson et al. [ 11 ], and 23% in an Iranian single-center cohort analyzed by Noei Teymoordash et al. [ 12 ]. Likewise, a large U.S. multi-institutional cohort [ 13 ] reported a similar overall burden of dMMR-related disease. However, unlike these previous reports, our study showed a different distribution of loss patterns wherein MLH1/PMS2 loss accounted for 50% (10/20) of patients with dMMR; this percentage is lower than that in several all-age cohorts. For example, Yamamoto et al. [ 9 ] found MLH1/PMS2 loss in 77.9% of dMMR cases in a Japanese hospital-based cohort, while Lawrence et al. [ 10 ] reported that 77% of dMMR cases in a Canadian universal screening program involved MLH1 hypermethylation. Building on the observations in a study about cancer risks for PMS2 -associated lynch syndrome [ 14 ], the 2025 NCCN Guidelines explicitly list only colorectal cancer and EC as PMS2 -associated malignancies [ 2 ]. This report helps explain the relatively lower diagnostic yield in cohorts enriched for PMS2 loss. Notably, even those aged under 50 years, one-half of the dMMR cases exhibited MLH1/PMS2 loss, indicating that methylation-driven disease remains common in young patients. Meanwhile, the presence of MSH2/MSH6 loss and MSH6 isolated loss suggests a meaningful non-methylated component. All of these findings indicate that in this study, restricting to patients aged below 50 years did not increase the overall proportion of dMMR relative to unselected, all-age populations and that the mechanistic composition may vary across settings. Although our study focused on patients younger than 50 years, the overall prevalence of dMMR was not higher than that reported in unselected, all-age cohorts. One possible explanation is the relatively high proportion of MLH1/PMS2 loss observed in our young cohort. Whether this finding reflects ethnic characteristics specific to the Japanese population or is simply due to the limited sample size remains unclear. Further investigation will be needed to clarify this point. The higher rate of adjuvant chemotherapy in patients with dMMR likely reflects case-mix, given that they more often had stage II–IV disease and non–G1 histology (G3 or special histotypes), both of which differed significantly between the two groups in our cohort. Meanwhile, the mechanistic composition of dMMR may differ by setting. In all-age cohorts, a substantial fraction of dMMR cases reflects somatic MLH1 promoter hypermethylation, typically manifesting as MLH1/PMS2 loss on IHC. In our cohort of 50 years of age and below, none had MLH1 isolated loss with retained PMS2 , and the overall dMMR prevalence was 23.5% (20/85). Given that MLH1 promoter methylation was not assessed, we could not distinguish sporadic epigenetic silencing from germline MLH1 variants in tumors with MLH1/PMS2 loss; therefore, age alone should not be used as a surrogate for either dMMR prevalence or mechanism. These data support universal tumor testing irrespective of age, with reflex MLH 1-methylation testing for MLH1/PMS2 loss and targeted germline evaluation for non-methylated loss patterns (e.g., MSH2/MSH6 or isolated PMS2 ). Histologically, dMMR tumors were more likely to be of a high grade (G2 or G3), a statistically significant finding that aligns with prior Japanese data. In a prospective observational study, Tsuruta et al. [ 15 ] reported that 54% of dMMR tumors in a Japanese cohort were grade 2 or 3. Clinically, fertility-sparing therapy is generally restricted to grade 1 endometrioid adenocarcinoma; therefore, we dichotomized histology as G1 versus others (G2–G3, carcinosarcoma). In this analysis, the distribution differed significantly between the pMMR and dMMR groups (48/17 and 6/14, respectively), indicating that dMMR tumors are both less often eligible for fertility-sparing management and, even when eligible, carries a higher-risk biology. This finding is consistent with prior reports showing that higher-grade disease is enriched in dMMR. It also aligns with outcomes in fertility-sparing cohorts, that is, the best overall response and 6-month complete response (CR) to progestin therapy were lower in the dMMR group. These data support the integration of MMR status into counseling for young patients considering conservative treatment; however, responses by specific loss patterns (e.g., MSH2/MSH6 vs. MLH1/PMS2) remain insufficiently defined [ 13 , 16 ]. Consistent with this clinical threshold, a multicenter, biomarker-stratified cohort by Chung et al. showed markedly poorer progestin responses in dMMR tumors: best overall response was 44.4% versus 82.2% in pMMR/p53-wild-type tumors, and 6-month CR was 11.1% versus 53.3% (both significant) [ 17 ]. These findings support routine MMR testing before recommending fertility-sparing therapy and suggest a cautious, individualized approach when treating dMMR. Notably, our study also documented that only few patients with dMMR conceived after achieving CR, indicating that conservative management is not categorically contraindicated but requires careful selection and close follow-up. Regarding family history, the presence of LS-related cancer in first-degree relatives was significantly associated with dMMR, reinforcing that detailed pedigree assessment is crucial. In our cohort, the dMMR rate was 40.7% among patients with first-degree relatives affected by LS-related cancers; this percentage was significantly higher than that in those without such a history (14.9%, p = 0.025). This pattern aligns with findings by Tsuruta et al. [ 15 ], who also reported that patients with positive family histories had high dMMR prevalence. While family history alone cannot determine MMR status, it remains a practical and low-cost screening tool, particularly when universal testing is limited. This finding again aligns with previous Japanese studies. Lastly, the pattern of MMR loss strongly influences genetic testing outcomes. All tested cases with MSH2/MSH6 loss were diagnosed with LS, supporting its established correlation. The diagnostic yield was lower for MLH1/PMS2 loss and MSH6 isolated loss. Overall, while dMMR prevalence in younger Japanese patients with EC is similar to that in other countries, the distribution pattern and clinical associations indicate unique features. To clarify the genetic and epigenetic landscape of this population, we need to incorporate methylation analysis and broader access to germline testing in future studies. This study has some limitations. First, the methylation of the MLH1 promoter was not analyzed; thus, we could not fully distinguish between sporadic and hereditary loss of MLH1/PMS2 . Second, germline testing was only performed in a few patients because it is not covered by the insurance in Japan, likely leading to LS underdiagnosis. Third, this study focused only in one institution, thereby having only a relatively small sample size, particularly for rare MMR loss subtypes. Consequently, the generalizability of our findings is limited. Nonetheless, this study has several strengths that help contextualize the findings. First, the prospective, consecutive enrollment of patients with written informed consent minimized selection and information biases compared with retrospective designs. Second, analysis of a young Japanese cohort (< 50 years) showed a dMMR prevalence comparable to that of all‑age groups, indicating that age restriction alone does not overestimate the overall frequency of dMMR. Third, pattern‑level resolution within the same cohort— MLH1/PMS2 loss, MSH2/MSH6 loss, and MSH6 isolated loss—together with germline results provided practical guidance for reflex testing and genetic counseling in routine care. In this prospective study, 23.5% of Japanese women aged under 50 years with EC exhibited dMMR. The distribution of MMR protein loss patterns differed in our cohort. Although MLH1/PMS2 loss accounted for 50% of dMMR cases, lower than the proportion reported in several all-age cohorts, this percentage was unexpectedly high, given that our study focused on a younger population, in whom methylation-driven disease would be expected to be less common. Additionally, dMMR tumors were more likely to be high-grade, and dMMR status was strongly associated with a positive family history of LS-related cancers, particularly among first-degree relatives. These findings emphasize the importance of integrating MMR protein testing, family history assessment, and appropriate genetic counseling in the clinical management of young patients with EC in Japan. Declarations Funding : None. Conflicts of interest: None. Acknowledgments: None. Data availability: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. 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Am J Obstet Gynecol 224: 370.e1-370.e13 Cite Share Download PDF Status: Published Journal Publication published 09 Apr, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 19 Jan, 2026 Reviewers agreed at journal 04 Nov, 2025 Reviewers invited by journal 04 Nov, 2025 Editor assigned by journal 11 Oct, 2025 First submitted to journal 03 Oct, 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. We do this by developing innovative software and high quality services for the global research community. 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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-7776818","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":539684216,"identity":"bb05db06-cf99-4e5f-a661-e481ad8f3174","order_by":0,"name":"Hidetaka 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Research","correspondingAuthor":false,"prefix":"","firstName":"Yoichi","middleName":"","lastName":"Aoki","suffix":""},{"id":539684230,"identity":"45f068b0-8ec9-422b-bcc2-c46c4751eb7c","order_by":14,"name":"Makiko Omi","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Makiko","middleName":"","lastName":"Omi","suffix":""},{"id":539684231,"identity":"b2a69e45-ce51-454d-8dee-9bd40bca8854","order_by":15,"name":"Sanshiro Okamoto","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Sanshiro","middleName":"","lastName":"Okamoto","suffix":""},{"id":539684232,"identity":"fb3ffe26-b040-435c-aaf2-40cd7e0f248e","order_by":16,"name":"Mayu Yunokawa","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Mayu","middleName":"","lastName":"Yunokawa","suffix":""},{"id":539684233,"identity":"b52e010a-66a4-491d-aa89-377ae30b7951","order_by":17,"name":"Arisa Ueki","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Arisa","middleName":"","lastName":"Ueki","suffix":""},{"id":539684234,"identity":"580e9f84-5b73-487d-8808-f49859182139","order_by":18,"name":"Akiko Tonooka","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Tonooka","suffix":""},{"id":539684235,"identity":"0360ccd3-8fd0-47e5-b58e-0ede6089935a","order_by":19,"name":"Hiroyuki Kanao","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Kanao","suffix":""}],"badges":[],"createdAt":"2025-10-04 02:08:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7776818/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7776818/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-026-03029-8","type":"published","date":"2026-04-09T15:59:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":95919997,"identity":"48a86e01-aa21-4b49-a5db-5f007ecf3331","added_by":"auto","created_at":"2025-11-14 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12:51:06","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":75595,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7776818/v1/b9038a88c31f69e965402ea0.html"},{"id":106810903,"identity":"841f35b7-22ba-4442-9997-5e68df24343a","added_by":"auto","created_at":"2026-04-13 16:17:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":662241,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7776818/v1/e285ba88-69dd-47d0-902e-90622dd20e0a.pdf"}],"financialInterests":"","formattedTitle":"Prevalence and clinicopathologic features of mismatch repair–deficient endometrial cancer in Japanese patients younger than 50 years: a single-center prospective observational study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLynch syndrome (LS) is an autosomal dominant hereditary disorder caused by germline pathogenic variants in mismatch repair (MMR) genes such as \u003cem\u003eMLH1, MSH2, MSH6\u003c/em\u003e, and \u003cem\u003ePMS2\u003c/em\u003e. Carriers of germline pathogenic variants in these causative genes have a high lifetime risk of developing multiple malignancies, including colorectal cancer, endometrial cancer (EC), ovarian cancer, gastric cancer, and urothelial cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Universal screening of MMR proteins via immunohistochemistry (IHC) has been widely adopted in Western countries and is recommended by several guidelines, given its cost-effectiveness and diagnostic yield [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Colonoscopic surveillance has significantly reduced the incidence and mortality of colorectal cancer in patients with LS, highlighting the importance of early identification [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Universal screening for MMR deficiency (dMMR) in EC is also rapidly gaining global acceptance; however, it has primarily been evaluated in unselected, mixed-age cohorts. Currently, age-restricted analyses are limited, and the detection rate of LS in younger patients remains unclear. This evidence gap is especially pronounced in Asian populations, underscoring the need for prospective data focused on younger women. Identifying LS during primary diagnosis is critical for both affected individuals and at-risk family members to early detect cancer, provide risk-reducing interventions, and improve the prognosis. In LS, EC is often the first diagnosed \u0026ldquo;sentinel\u0026rdquo; cancer; hence, its proper evaluation plays a central role in hereditary cancer diagnosis. Although dMMR has been reported to be prevalent in EC, many previous studies have focused on advanced or recurrent cases or on general populations without age restriction. To date, prospective data focusing exclusively on women aged under 50 years, including those from Asia, remain limited. In this study, we aimed to prospectively evaluate the prevalence and clinical characteristics of dMMR among Japanese patients aged 50 years and below who were diagnosed with EC.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eThis study obtained approval from the Institutional Review Board of our institution (IRB No. : 2021-GB-076) and conformed to the principles of the Declaration of Helsinki. MMR IHC for study purposes was performed only in patients who provided written informed consent. IHC categories were as follows: loss of \u003cem\u003eMLH1/PMS2\u003c/em\u003e, loss of \u003cem\u003eMSH2/MSH6\u003c/em\u003e, isolated loss of \u003cem\u003eMSH6\u003c/em\u003e, and isolated loss of \u003cem\u003ePMS2\u003c/em\u003e. When dMMR was identified, patients were referred to the Department of Clinical Genetics, where they received genetic counseling. Based on this, the option of germline testing for Lynch syndrome (LS) was discussed.\u003c/p\u003e\u003cp\u003eThis prospective observational study enrolled patients aged under 50 years who were diagnosed with EC at our institution between November 2020 and December 2024. MMR proteins (\u003cem\u003eMLH1, MSH2, MSH6\u003c/em\u003e, and \u003cem\u003ePMS2\u003c/em\u003e) from surgical specimens obtained at primary surgery were analyzed by IHC. IHC was also performed on biopsy specimens obtained during diagnosis from patients managed with fertility-sparing therapy without hysterectomy. The following clinical data were collected: age at diagnosis, histological grade (G1 to G3, carcinosarcoma, etc.), family history (the presence and familial aggregation of LS-related cancers), and genetic testing results. LS-related cancers included colorectal cancer (including rectal cancer), brain tumors, biliary tract cancer, gastric cancer, pancreatic cancer, small intestinal cancer, ovarian cancer, and cancers of the renal pelvis or ureter. Family history was classified into three categories: no LS-related cancer, LS-related cancer in a first-degree relative, and LS-related cancer only in second-degree relatives. Regarding MMR status, dMMR was considered only when loss of nuclear expression on IHC was unequivocal and conformed to predefined patterns. Conversely, equivocal/patchy/weak staining, subclonal loss of uncertain significance, or internal-control failure were not counted as dMMR, thereby categorized as indeterminate. Then, dMMR cases were subclassified as \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss, \u003cem\u003eMSH2/MSH6\u003c/em\u003e loss, \u003cem\u003eMSH6\u003c/em\u003e isolated loss, or \u003cem\u003ePMS2\u003c/em\u003e isolated loss. The causative genes were estimated using descriptive and comparative statistics. To assess the association between MMR status and clinicopathological features, we conducted chi-squared test.\u003c/p\u003e\u003cp\u003eStatistical analyses were performed using the chi-squared test to evaluate associations between MMR status and categorical clinicopathological variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated where appropriate. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. All analyses were conducted using R version 3.6.1.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 85 patients included in this study, 20 (23.5%) had dMMR according to IHC. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the baseline patient characteristics by MMR status. The frequency of pregnancy (G\u0026thinsp;\u0026ge;\u0026thinsp;1: 40.0% vs. 30.8%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.587) and delivery (P\u0026thinsp;\u0026ge;\u0026thinsp;1: 20.0% vs. 27.7%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.572), as well as concurrent ovarian cancer (30.0% vs. 20.0%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.528), was similar between the pMMR and dMMR groups. FIGO stage distribution differed between such groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021). Stage I comprised the vast majority (53/65, 81.5%) in the pMMR group but was significantly less frequent in the dMMR group (11/20, 55.0%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035). Accordingly, stages II\u0026ndash;IV were more common in dMMR (9/20, 45.0%) than in pMMR (12/65, 18.5%). Moreover, postoperative chemotherapy was more common in dMMR (13/20 [65.0%]) than in pMMR (16/65 [24.6%]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0023; OR, 5.69; 95% CI, 1.93\u0026ndash;16.72). At our institution, adjuvant chemotherapy is generally administered to patients with EC with an intermediate or higher risk of recurrence, providing clinical context for the observed pattern.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline patient characteristics by MMR status\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003epMMR (n\u0026thinsp;=\u0026thinsp;65)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003edMMR (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNotes\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years (median [IQR])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (39\u0026ndash;46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44 (41\u0026ndash;48)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.457\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003egravida\u0026thinsp;\u0026ge;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (30.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.587\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eparas\u0026thinsp;\u0026ge;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (27.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.572\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFamily history category\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\u003cp\u003e0.038\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eChi-square, Cat0/1/2 overall\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (35%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (24.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (55%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCat1 vs Cat0: p\u0026thinsp;=\u0026thinsp;0.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFisher\u003c/p\u003e\u003cp\u003e(dMMR rate 11/27 vs 7/46)\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=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (15.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConcurrent ovarian cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (30%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.528\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistology\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\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFisher, G1 vs others\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48 (73.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (30.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (12.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (40.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (9.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (30.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\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\u003e3 (4.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO stage\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\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFisher, I vs II\u0026ndash;IV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53 (81.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (55%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (6.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (30%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (7.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (4,6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eadjuvant chemotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (24.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (65%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the IHC patterns of the 20 dMMR cases, of which 10 (50%) had \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss, 5 (25%) had \u003cem\u003eMSH2/MSH6\u003c/em\u003e loss, and 5 (25%) had \u003cem\u003eMSH6\u003c/em\u003e isolated loss. None had \u003cem\u003ePMS2\u003c/em\u003e isolated loss. Regarding histological characteristics, grade 1 endometrioid adenocarcinoma (73.8%) was found in most of those in the pMMR group but only 30% in the dMMR group. Conversely, grade 2 (40%) and grade 3 (30%) tumors were more common among dMMR cases. When grades were dichotomized as G1 versus G2\u0026ndash;G3, the distribution differed significantly between such groups (pMMR: 48/17 vs. dMMR: 6/14; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). With regard to the association with LS-related family history, dMMR was most prevalent in patients with first-degree relatives affected by LS (category 1) (40.7%), followed by those with only second-degree relatives affected (category 2) (16.7%) and those without an LS-related family history (category 0) (14.9%). Their difference was statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025). Of the 10 patients with \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss, 3 underwent germline testing, and among them, only 1 was diagnosed with LS (33.3%). Additionally, 3 of the 5 patients with \u003cem\u003eMSH2/MSH6\u003c/em\u003e loss underwent testing, and all of them were found to have LS (100%).\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\u003edMMR prevalence and IHC loss patterns across representative universal-screening cohorts\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=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\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\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCohort / Study\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN (population)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003edMMR prevalence\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMLH1\u0026thinsp;+\u0026thinsp;PMS2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMSH2 and MSH6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMSH2-only\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMSH6-only\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePMS2-only\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHospital-based (JJCO 2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e395 (all-comers)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMedian 59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17.2% (68/395)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e77.9% (53/68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e13.2% (9/68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2.9% (2/68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e4.4% (3/68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.5% (1/68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCanada\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMUSE (Curr Oncol 2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e261 (all-comers)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;70 vs\u0026thinsp;\u0026ge;\u0026thinsp;70 reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e26.4% (69/261)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e82.6% (57/69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e8.7% (6/69)\u003c/p\u003e\u003cp\u003eMSH2 and/or MSH6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4.3% (3/69)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSweden\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNational program (Hered Cancer Clin Pract 2024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e221 (all-comers)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNot restricted\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24% (54/221)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e83.3% (45/54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e16.7% (9/54) MSH2 and/or MSH6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingle-center (Caspian J Intern Med 2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100 (all-comers)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMean 56.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e23% (23/100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e17.4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17.4% (MSH2 loss)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e13.0% (reported as PMS2/MSH2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMulti-institutional (Gynecol Oncol 2020)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,018 (all-comers)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNot restricted\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e28.4% (289/1018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCurrent study (\u0026le;\u0026thinsp;50 y)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e85 (\u0026le;\u0026thinsp;50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e23.5% (20/85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50.0% (10/20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e25.0% (5/20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e25.0% (5/20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003cem\u003eNA: not applicable\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\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\u003eGermline testing by immunohistochemistry staining loss pattern among dMMR patients\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=\"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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIHC loss pattern\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTested\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003epositive\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMLH1\u0026thinsp;+\u0026thinsp;PMS2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (30%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMSH2\u0026thinsp;+\u0026thinsp;MSH6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (100%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMSH6-only\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (50%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (62.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe prevalence of dMMR in our age-restricted cohort (20/85 (23.5%) was unexpectedly comparable to rates reported in unselected, all-age series across regions (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Reported rates included 17.2% in a Japanese hospital-based cohort by Yamamoto et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], 26.4% in a Canadian universal-screening program described by Lawrence et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], 24% in a Swedish national implementation study by Andersson et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and 23% in an Iranian single-center cohort analyzed by Noei Teymoordash et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Likewise, a large U.S. multi-institutional cohort [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] reported a similar overall burden of dMMR-related disease. However, unlike these previous reports, our study showed a different distribution of loss patterns wherein \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss accounted for 50% (10/20) of patients with dMMR; this percentage is lower than that in several all-age cohorts. For example, Yamamoto et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] found \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss in 77.9% of dMMR cases in a Japanese hospital-based cohort, while Lawrence et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] reported that 77% of dMMR cases in a Canadian universal screening program involved \u003cem\u003eMLH1\u003c/em\u003e hypermethylation. Building on the observations in a study about cancer risks for \u003cem\u003ePMS2\u003c/em\u003e-associated lynch syndrome [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], the 2025 NCCN Guidelines explicitly list only colorectal cancer and EC as \u003cem\u003ePMS2\u003c/em\u003e-associated malignancies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This report helps explain the relatively lower diagnostic yield in cohorts enriched for \u003cem\u003ePMS2\u003c/em\u003e loss. Notably, even those aged under 50 years, one-half of the dMMR cases exhibited \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss, indicating that methylation-driven disease remains common in young patients. Meanwhile, the presence of \u003cem\u003eMSH2/MSH6\u003c/em\u003e loss and \u003cem\u003eMSH6\u003c/em\u003e isolated loss suggests a meaningful non-methylated component. All of these findings indicate that in this study, restricting to patients aged below 50 years did not increase the overall proportion of dMMR relative to unselected, all-age populations and that the mechanistic composition may vary across settings. Although our study focused on patients younger than 50 years, the overall prevalence of dMMR was not higher than that reported in unselected, all-age cohorts. One possible explanation is the relatively high proportion of MLH1/PMS2 loss observed in our young cohort. Whether this finding reflects ethnic characteristics specific to the Japanese population or is simply due to the limited sample size remains unclear. Further investigation will be needed to clarify this point. The higher rate of adjuvant chemotherapy in patients with dMMR likely reflects case-mix, given that they more often had stage II\u0026ndash;IV disease and non\u0026ndash;G1 histology (G3 or special histotypes), both of which differed significantly between the two groups in our cohort.\u003c/p\u003e\u003cp\u003eMeanwhile, the mechanistic composition of dMMR may differ by setting. In all-age cohorts, a substantial fraction of dMMR cases reflects somatic \u003cem\u003eMLH1\u003c/em\u003e promoter hypermethylation, typically manifesting as \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss on IHC. In our cohort of 50 years of age and below, none had \u003cem\u003eMLH1\u003c/em\u003e isolated loss with retained \u003cem\u003ePMS2\u003c/em\u003e, and the overall dMMR prevalence was 23.5% (20/85). Given that \u003cem\u003eMLH1\u003c/em\u003e promoter methylation was not assessed, we could not distinguish sporadic epigenetic silencing from germline \u003cem\u003eMLH1\u003c/em\u003e variants in tumors with \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss; therefore, age alone should not be used as a surrogate for either dMMR prevalence or mechanism. These data support universal tumor testing irrespective of age, with reflex \u003cem\u003eMLH\u003c/em\u003e1-methylation testing for \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss and targeted germline evaluation for non-methylated loss patterns (e.g., \u003cem\u003eMSH2/MSH6\u003c/em\u003e or isolated \u003cem\u003ePMS2\u003c/em\u003e).\u003c/p\u003e\u003cp\u003eHistologically, dMMR tumors were more likely to be of a high grade (G2 or G3), a statistically significant finding that aligns with prior Japanese data. In a prospective observational study, Tsuruta et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] reported that 54% of dMMR tumors in a Japanese cohort were grade 2 or 3. Clinically, fertility-sparing therapy is generally restricted to grade 1 endometrioid adenocarcinoma; therefore, we dichotomized histology as G1 versus others (G2\u0026ndash;G3, carcinosarcoma). In this analysis, the distribution differed significantly between the pMMR and dMMR groups (48/17 and 6/14, respectively), indicating that dMMR tumors are both less often eligible for fertility-sparing management and, even when eligible, carries a higher-risk biology. This finding is consistent with prior reports showing that higher-grade disease is enriched in dMMR. It also aligns with outcomes in fertility-sparing cohorts, that is, the best overall response and 6-month complete response (CR) to progestin therapy were lower in the dMMR group. These data support the integration of MMR status into counseling for young patients considering conservative treatment; however, responses by specific loss patterns (e.g., \u003cem\u003eMSH2/MSH6\u003c/em\u003e vs. \u003cem\u003eMLH1/PMS2)\u003c/em\u003e remain insufficiently defined [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Consistent with this clinical threshold, a multicenter, biomarker-stratified cohort by Chung et al. showed markedly poorer progestin responses in dMMR tumors: best overall response was 44.4% versus 82.2% in pMMR/p53-wild-type tumors, and 6-month CR was 11.1% versus 53.3% (both significant) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These findings support routine MMR testing before recommending fertility-sparing therapy and suggest a cautious, individualized approach when treating dMMR. Notably, our study also documented that only few patients with dMMR conceived after achieving CR, indicating that conservative management is not categorically contraindicated but requires careful selection and close follow-up. Regarding family history, the presence of LS-related cancer in first-degree relatives was significantly associated with dMMR, reinforcing that detailed pedigree assessment is crucial. In our cohort, the dMMR rate was 40.7% among patients with first-degree relatives affected by LS-related cancers; this percentage was significantly higher than that in those without such a history (14.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025). This pattern aligns with findings by Tsuruta et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], who also reported that patients with positive family histories had high dMMR prevalence. While family history alone cannot determine MMR status, it remains a practical and low-cost screening tool, particularly when universal testing is limited. This finding again aligns with previous Japanese studies. Lastly, the pattern of MMR loss strongly influences genetic testing outcomes. All tested cases with \u003cem\u003eMSH2/MSH6\u003c/em\u003e loss were diagnosed with LS, supporting its established correlation. The diagnostic yield was lower for \u003cem\u003eMLH1/PMS2\u003c/em\u003e loss and \u003cem\u003eMSH6\u003c/em\u003e isolated loss. Overall, while dMMR prevalence in younger Japanese patients with EC is similar to that in other countries, the distribution pattern and clinical associations indicate unique features. To clarify the genetic and epigenetic landscape of this population, we need to incorporate methylation analysis and broader access to germline testing in future studies.\u003c/p\u003e\u003cp\u003eThis study has some limitations. First, the methylation of the \u003cem\u003eMLH1\u003c/em\u003e promoter was not analyzed; thus, we could not fully distinguish between sporadic and hereditary loss of \u003cem\u003eMLH1/PMS2\u003c/em\u003e. Second, germline testing was only performed in a few patients because it is not covered by the insurance in Japan, likely leading to LS underdiagnosis. Third, this study focused only in one institution, thereby having only a relatively small sample size, particularly for rare MMR loss subtypes. Consequently, the generalizability of our findings is limited. Nonetheless, this study has several strengths that help contextualize the findings. First, the prospective, consecutive enrollment of patients with written informed consent minimized selection and information biases compared with retrospective designs. Second, analysis of a young Japanese cohort (\u0026lt;\u0026thinsp;50 years) showed a dMMR prevalence comparable to that of all‑age groups, indicating that age restriction alone does not overestimate the overall frequency of dMMR. Third, pattern‑level resolution within the same cohort\u0026mdash;\u003cem\u003eMLH1/PMS2\u003c/em\u003e loss, \u003cem\u003eMSH2/MSH6\u003c/em\u003e loss, and \u003cem\u003eMSH6\u003c/em\u003e isolated loss\u0026mdash;together with germline results provided practical guidance for reflex testing and genetic counseling in routine care.\u003c/p\u003e\u003cp\u003eIn this prospective study, 23.5% of Japanese women aged under 50 years with EC exhibited dMMR. The distribution of MMR protein loss patterns differed in our cohort. Although MLH1/PMS2 loss accounted for 50% of dMMR cases, lower than the proportion reported in several all-age cohorts, this percentage was unexpectedly high, given that our study focused on a younger population, in whom methylation-driven disease would be expected to be less common. Additionally, dMMR tumors were more likely to be high-grade, and dMMR status was strongly associated with a positive family history of LS-related cancers, particularly among first-degree relatives. These findings emphasize the importance of integrating MMR protein testing, family history assessment, and appropriate genetic counseling in the clinical management of young patients with EC in Japan.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSingh S, Rensnick KE (2013) Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers. PLoS ONE 8: e79737\u003c/li\u003e\n\u003cli\u003ehttps://www.nccn.org/professionals/physician_gls/pdf/genetics_ceg.pdf\u003c/li\u003e\n\u003cli\u003ehttps://www.nice.org.uk/guidance/dg42\u003c/li\u003e\n\u003cli\u003eConcin N, Matias-Guiu X, Cibula D, et al (2025) ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma: update 2025. Lancet Oncol 26: e423-e435\u003c/li\u003e\n\u003cli\u003eStjepanovic N, Moreira L, Carneiro F, et al (2019) Hereditary gastrointestinal cancers: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 30: 1558-1571\u003c/li\u003e\n\u003cli\u003ehttps://www.cosa.org.au/advocacy/position-statements/tumour-screening-for-mismatch-repair-deficiency-lynch-syndrome/?utm_source=chatgpt.com\u003c/li\u003e\n\u003cli\u003eAronson M, Palma L, Semotiuk K, et al (2025) Canadian consensus for the assessment and testing of Lynch syndrome. J Med Genet 62: 326-334\u003c/li\u003e\n\u003cli\u003eCastillo-Iturra J, S\u0026aacute;nchez A, Balaguer F (2024) Colonoscopic surveillance in Lynch syndrome: guidelines in perspective. Fam Cancer 23: 459-468\u003c/li\u003e\n\u003cli\u003eYamamoto A, Yamaguchi T, Suzuki O, 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: 60-69\u003c/li\u003e\n\u003cli\u003eLawrence J, Richer L, Arseneau J, et al (2021) Mismatch repair universal screening of endometrial cancers (MUSE) in a Canadian cohort. Curr Oncol 28: 509-522\u003c/li\u003e\n\u003cli\u003eAndersson E, Ker\u0026auml;nen A, Lagerstedt-Robinson K, et al (2024) Universal testing in endometrial cancer in Sweden. Hered Cancer Clin Pract 22: 14\u003c/li\u003e\n\u003cli\u003eNoei Teymoordash S, Arab M, Bahar M, Ebrahimi A, et al (2022) Screening of Lynch syndrome in endometrial cancer in Iranian population with mismatch repair protein by immunohistochemistry. Caspian J Intern Med 13: 772-779\u003c/li\u003e\n\u003cli\u003eCarr C, Son J, Yao M, et al (2020) Clinicopathologic characteristics and outcomes of endometrial cancer patients with mismatch repair deficiency in the era of universal Lynch syndrome screening. Gynecol Oncol 159: 712-720\u003c/li\u003e\n\u003cli\u003eTen Broeke SW, van der Klift HM, Tops CMJ, et al (2018) Cancer risks for \u003cem\u003ePMS2\u003c/em\u003e-associated lynch syndrome. J Clin Oncol 36: 2961-2968\u003c/li\u003e\n\u003cli\u003eTsuruta T, Todo Y, Yamada R, et al (2022) Initial screening by immunohistochemistry is effective in universal screening for Lynch syndrome in endometrial cancer patients: a prospective observational study. Jpn J Clin Oncol 52: 752-758\u003c/li\u003e\n\u003cli\u003eRing KL, Connor EV, Atkins KA, et al (2013) Women 50 years or younger with endometrial cancer: the argument for universal mismatch repair screening and potential for targeted therapeutics. Int J Gynecol Cancer 23: 853-860\u003c/li\u003e\n\u003cli\u003eChung YS, Woo HY, Lee JY, et al (2021) Mismatch repair status influences response to fertility-sparing treatment of endometrial cancer. Am J Obstet Gynecol 224: 370.e1-370.e13\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":"dMMR, endometrial cancer, IHC, Lynch syndrome, universal screening","lastPublishedDoi":"10.21203/rs.3.rs-7776818/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7776818/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eUniversal tumor testing is increasingly recommended for Lynch syndrome (LS). However, data involving younger Japanese patients are still limited. This study aimed to prospectively evaluate the prevalence and clinicopathologic profile of DNA mismatch repair (MMR)\u0026ndash;deficient (dMMR) endometrial cancers (EC) in patients aged under 50 years, and characterize immunohistochemical (IHC) loss patterns and genetic testing results.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eConsecutive patients with EC aged under 50 years were prospectively enrolled at a single Japanese institution. Diagnostic specimens underwent MMR IHC (\u003cem\u003eMLH1, MSH2, MSH6\u003c/em\u003e, and \u003cem\u003ePMS2\u003c/em\u003e). Clinicopathologic variables were compared between proficient MMR (pMMR) and dMMR.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 85 patients, 20 (23.5%) had dMMR. Grades differed when dichotomized as G1 versus G2\u0026ndash;G3 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). FIGO stage distribution also varied between groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021); stage I was 53/65 (81.5%) in pMMR and 11/20 (55.0%) in dMMR (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035). Among dMMR tumors, IHC patterns were loss of \u003cem\u003eMLH1/PMS2\u003c/em\u003e (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10), loss of \u003cem\u003eMSH2/MSH6\u003c/em\u003e (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5), and isolated loss of \u003cem\u003eMSH6\u003c/em\u003e (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5). Of the 8 (40.0%) patients with dMMR who underwent germline testing, 5 had LS (\u003cem\u003eMLH1/PMS2\u003c/em\u003e loss: 1/3; \u003cem\u003eMSH2/MSH6\u003c/em\u003e loss: 3/3; \u003cem\u003eMSH6\u003c/em\u003e isolated loss: 1/2). The overall dMMR prevalence in this young cohort was comparable to that in all-age series from multiple regions.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn this prospective Japanese cohort, approximately one in four patients with EC had dMMR, with clinicopathologic features skewing toward a higher grade. Notably, many dMMR tumors were grade 2\u0026ndash;3, thereby not eligible for fertility-sparing treatment.\u003c/p\u003e","manuscriptTitle":"Prevalence and clinicopathologic features of mismatch repair–deficient endometrial cancer in Japanese patients younger than 50 years: a single-center prospective observational study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-14 12:51:02","doi":"10.21203/rs.3.rs-7776818/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2026-01-19T07:22:45+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-11-04T10:46:52+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-04T09:09:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-11T14:13:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-10-03T22:06:23+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":"3ac5056e-20e4-485b-a31b-b1f894787f96","owner":[],"postedDate":"November 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:15:36+00:00","versionOfRecord":{"articleIdentity":"rs-7776818","link":"https://doi.org/10.1007/s10147-026-03029-8","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2026-04-09 15:59:28","publishedOnDateReadable":"April 9th, 2026"},"versionCreatedAt":"2025-11-14 12:51:02","video":"","vorDoi":"10.1007/s10147-026-03029-8","vorDoiUrl":"https://doi.org/10.1007/s10147-026-03029-8","workflowStages":[]},"version":"v1","identity":"rs-7776818","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7776818","identity":"rs-7776818","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}