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

## TL;DR

This review explains how hereditary factors like Lynch syndrome increase the risk of endometrial cancer and highlights the importance of genetic testing for early detection and prevention.

## Contribution

The paper provides a comprehensive overview of hereditary endometrial cancer, emphasizing Lynch syndrome and emerging genetic predispositions with clinical guidelines.

## Key findings

- Lynch syndrome is the most significant hereditary cause of endometrial cancer, with up to 71% lifetime risk for MSH6 mutation carriers.
- Hereditary endometrial cancer is often underdiagnosed, missing opportunities for prevention and targeted treatment.
- Rare genetic conditions like Cowden syndrome and Li–Fraumeni syndrome also contribute to hereditary endometrial cancer risk.

## 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.