Molecular analysis of the evolutionary history of endometrial and ovarian carcinoma in Lynch syndrome

Sep 24, 2026

Lynch syndrome (LS) is a major cause of hereditary gynecological cancers, yet the molecular steps from mismatch repair (MMR) defects to malignancy are not fully defined. Deep sequencing of a 1,000-gene panel was performed on retrospective specimens from 33 LS carriers with endometrial or ovarian carcinoma, including consecutive atypical endometrial hyperplasia samples. Carcinomas were largely MMR-deficient, showed frequent second hits, and hyperplasia closely matched carcinoma profiles. Some shared cancer variants were detectable in histologically normal endometrium years before diagnosis, clarifying evolutionary trajectories of LS-associated tumorigenesis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Background and study goal

Cohort, sequencing strategy, and sample design

Key molecular findings

Interpretation and implications

Introduction

Epidemiology and lifetime risk in general vs Lynch syndrome

Deficient MMR and timing of gynecological cancers

Histological context and proposed stepwise development

DOI: 10.1002/ijc.70074 RES EARCH A RTICLE C a ncer Geneti cs an d E p igen e ti cs Molecular analysis of the evolutionary history of endometrial and ovarian carcinoma in Lynch syndrome Anni K. Kauppinen 1 | Alisa P. Olkinuora 1 | Jukka-Pekka Mecklin 2,3 | Päivi T. Peltomäki 1,4 1Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland 2Department of Education & Research, The Wellbeing Services of Central Finland, Jyväskylä, Finland 3Department of Sports and Health Sciences, Jyväskylä University, Jyväskylä, Finland 4HUSLAB Laboratory of Genetics, HUS Diagnostic Center, HUS, Helsinki University Hospital, Helsinki, Finland Correspondence Anni K. Kauppinen, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland. Email: [anni.k.kauppinen@helsinki.fi](anni.k.kauppinen@helsinki.fi) Funding information Sigrid Juséliuksen Säätiö; University of Helsinki Doctoral Programme in Biomedicine; The Academy of Finland, Grant/Award Number: 330606; Syöpäsäätiö; Biomedicum Helsinki-säätiö; Jane ja Aatos Erkon Säätiö Abstract Lynch syndrome (LS) is a prevalent cause of hereditary gynecological cancers. 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-associated 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 years (0–15 years) . Of carcinomas, all but one (41/42, 98%) were MMR-deficient 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-synonymous mutations per megabase) was 36/42 (86%) among carcinomas and 15/22 (68%) among hyperplasia specimens (statistically nonsignificant difference) . In individual patients, cancer-associated 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. KEYWOR DS endometrial carcinoma, Lynch syndrome, ovarian carcinoma, panel sequencing, somatic variant Abbreviations: AH, atypical hyperplasia; B, blood; CAH, complex atypical hyperplasia; CCEC, clear cell endometrial carcinoma; CCOC, clear cell ovarian carcinoma; CH, complex hyperplasia without atypia; CxEC, cervical adenocarcinoma; EC, endometrial carcinoma; EEC, endometrioid endometrial carcinoma; EOC, endometrioid ovarian carcinoma; FT, normal fallopian tube; IGV, Integrative Genomics Viewer; IHC, immunohistochemistry; LOH, loss of heterozygosity; LS, Lynch syndrome; MMR, mismatch repair; MSI, microsatellite instability; N, normal; NE, normal endometrium; OC, ovarian carcinoma; SH, simple hyperplasia; T, tumor; TMB, tumor mutational burden; VAF, variant allele frequency. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Author(s) . International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. What's New? Lynch syndrome is a prevalent

FAQs

What was the main aim of this molecular study in Lynch syndrome?

To map molecular alterations that precede endometrial and ovarian cancer by analyzing consecutive surveillance specimens leading up to diagnosis.

How were MMR defects and second hits assessed?

MMR deficiency was evaluated using microsatellite instability and immunohistochemical analysis, and second hits were inferred from loss of heterozygosity or somatic variants in MMR genes.

What relationship did atypical endometrial hyperplasia show compared with carcinoma?

Atypical hyperplasia closely resembled endometrial and ovarian carcinoma regarding MMR deficiency, second-hit frequency, and mutational profiles, including similar tumor mutation burdens and top mutant genes.

Sep 24, 2026

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