Hereditary Endometrial Cancer - Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions - A Comprehensive Review with Clinical and Laboratory Guidelines

Sep 23, 2026

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Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with increasing incidence driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. While most cases are sporadic, 2–5% arise from hereditary cancer syndromes, chiefly Lynch syndrome, caused by germline DNA mismatch repair (MMR) gene mutations. The review details genetic mechanisms, inheritance patterns, diagnostic approaches, and clinical implications for screening, genetic counselling, and treatment optimisation, emphasizing molecular recognition and the continuing underdiagnosis that limits prevention.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages39

Reading Time1 h 38 min

AccessFree to download

Introduction

Hereditary cancer syndromes and Lynch syndrome overview

Molecular pathology, immunogenomics, and clinical relevance

Abstract

Genetic mechanisms, diagnosis, and clinical implications

Review Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions—A Comprehensive Review with Clinical and Laboratory Guidelines Andrzej Kluk 1, Hanna Gryczka 1, Małgorzata Braszka 2, Rafał Ałtyn 3, Hanna Markiewicz 4,5, *, Jan K. ´Sl˛eak 1, Ewa Dwojak 1, Joanna Czerniak 6, Paweł Zieli ´nski 1, Bartosz J. Płachno 7 and Paula Dobosz 1 Academic Editor: Rafael Coveñas Rodríguez Received: 28 November 2025 Revised: 13 January 2026 Accepted: 13 January 2026 Published: 28 January 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Pathomorphology, Poznan University of Medical Sciences, 60-355 Poznan, Poland; [akluk@interia.pl](akluk@interia.pl) (A.K.); [jankazimierzslezak@gmail.com](jankazimierzslezak@gmail.com) (J.K.´S .); torakochirurg.zielinski@gmail.com (P.Z.) 2 Cairns Base Hospital, Cairns, QLD 4870, Australia 3 IT Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland 4 Department of Histology and Embryology, Faculty of Medicine, Medical University of Warsaw, 02-004 Warsaw, Poland 5 Department of Methodology, Faculty of Medicine, Medical University of Warsaw, 02-004 Warsaw, Poland 6 Centre of Experimental Medicine, Poznan University of Medical Sciences, 60-806 Poznan, Poland 7 Institute of Botany, Faculty of Biology, Jagiellonian University, 30-387 Cracow, Poland; [bartosz.plachno@uj.edu.pl](bartosz.plachno@uj.edu.pl) * Correspondence: [s090439@student.wum.edu.pl](s090439@student.wum.edu.pl) Abstract Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with a rising incidence largely driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. Although most cases are sporadic, approximately 2–5% are associated with hereditary cancer syndromes, of which Lynch syndrome represents the most important contributor. Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes and is associated with a substantially increased lifetime risk of endometrial cancer, reaching up to 71% in carriers of MutS homologue 6 (MSH6) mutations. Hereditary cancer predisposition typically follows an autosomal dominant inheritance pattern and may be suspected based on clinical warning signs such as early disease onset, multiple primary malignancies, a strong family history, or the presence of microsatellite instability in tumour tissue. In addition to Lynch syndrome, rarer genetic conditions—including Cowden syndrome (PTEN), Li–Fraumeni syndrome (TP53), polymerase proofreading–associated polyposis (POLE/POLD1), and hereditary breast and ovarian cancer syndromes (BRCA1/2)—also contribute to hereditary endometrial cancer risk. Recognition of these genetic backgrounds is essential for accurate diagnosis, personalised surveillance, and the implementation of targeted preventive and therapeutic strategies. Despite major advances in molecular diagnostics, hereditary endometrial cancer remains frequently underdiagnosed, leading to missed opportunities for cancer prevention among affected individuals and their families. This comprehensive review summarises current evidence on hereditary predispositions to endometrial cancer, with a particular emphasis on Lynch syndrome, and discusses underlying genetic mechanisms, inheritance patterns, diagnostic strategies, and clinical implications for screening, genetic counselling, and treatment optimisation. Keywords: endometrial cancer; Lynch syndrome; hereditary cancer syndromes; mismatch repair deficiency; genetic predisposition 1. Introduction Endometrial cancer is among the most common gynaecologic malignancies in highincome countries. Its development is strongly influenced by factors that prolong oestrogen exposure without the counterbalancing effect of pr

FAQs

What causes Lynch syndrome and how does it increase endometrial cancer risk?

Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes. Carriers have a substantially increased lifetime risk of endometrial cancer, with reported risks reaching up to 71% for MSH6 mutation carriers.

What clinical features can suggest an inherited cancer predisposition in endometrial cancer patients?

The document notes warning signs such as early disease onset, multiple primary malignancies, strong family history, and microsatellite instability in tumour tissue.

Why is molecular recognition important for managing hereditary endometrial cancer?

Mismatch repair deficiency and microsatellite instability define Lynch syndrome–associated cancers and support tumour classification, prognostication, and therapy decisions. This recognition also enables targeted surveillance, genetic counselling, and preventive strategies for affected families.

Sep 23, 2026

Uploaded by Aria