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DNA mismatch repair (MMR) defects are important players in LS tumorigenesis, but the developmental steps leading to malignancy are incompletely understood. We undertook a deep sequencing approach with a panel of ~1,000 cancer\u2010associated genes to detect somatic changes in retrospective specimens from 33 LS carriers who had developed endometrial carcinoma (EC) or ovarian carcinoma (OC). Consecutive samples of atypical endometrial hyperplasia (AH) and EC or OC (64 samples plus blood) were available from a screening period of 15\u2009years (0\u201315\u2009years). Of carcinomas, all but one (41\/42, 98%) were MMR\u2010deficient by microsatellite instability or immunohistochemical analysis, and 86% (36\/42) showed loss of heterozygosity or somatic variants of MMR genes as putative second hits. AH closely resembled EC and OC with respect to MMR deficiency (20\/22, 91%) and the presence of second hits (16\/22, 73%); moreover, the average tumor mutation burdens and top mutant genes were largely similar in hyperplasia and carcinoma. The proportion of hypermutated tumors (over 10 somatic non\u2010synonymous mutations per megabase) was 36\/42 (86%) among carcinomas and 15\/22 (68%) among hyperplasia specimens (statistically non\u2010significant difference). In individual patients, cancer\u2010associated genes revealed varying degrees of somatic variant sharing between consecutive specimens of hyperplasia and carcinoma (10\/19, 53%), and in some, such variants were detectable in histologically normal endometrium (9\/19, 47%) too, one or several years before carcinoma. Our results shed light on the evolutionary trajectories of gynecological cancer development in LS.<\/jats:p>","DOI":"10.1002\/ijc.70074","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T12:56:23Z","timestamp":1754571383000},"page":"2294-2308","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular analysis of the evolutionary history of endometrial and ovarian carcinoma in Lynch syndrome"],"prefix":"10.1002","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0662-7483","authenticated-orcid":false,"given":"Anni K.","family":"Kauppinen","sequence":"first","affiliation":[{"name":"Department of Medical and Clinical Genetics, Medicum University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3987-9924","authenticated-orcid":false,"given":"Alisa 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