Lynch Syndrome in Focus - A Multidisciplinary Review of Cancer Risk, Clinical Management, and Special Populations

Sep 24, 2026

Uploaded by OmBimo

Lynch syndrome (LS), the most common autosomal dominant hereditary colorectal cancer syndrome, arises from germline pathogenic variants in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and EPCAM deletions. This narrative review synthesizes the molecular basis, clinical presentation, and tumor spectrum, emphasizing how gene-specific risk shapes personalized cancer surveillance and prevention. It also covers diagnostic strategies using MSI and immunohistochemistry, evaluates extracolonic risks including gynecologic cancers, and summarizes emerging colorectal and immunotherapy approaches to improve patient outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages43

Reading Time1 h 48 min

AccessFree to download

1. Overview of Lynch Syndrome

1.1. Historical Background

1.2. Molecular Basis and Genetics

Review Lynch Syndrome in Focus: A Multidisciplinary Review of Cancer Risk, Clinical Management, and Special Populations Seyma Eroglu 1, Ilhan Birsenogul 2, Alexandra P. Bowen 3,4,5, Joseph F. Doyle 4,6,7, Stephen E. Pupkin 3,4,5, Joaquin Villar 3,8,9, Christopher M. Tarney 10,11,12, Edwin Gandia 6,13, Danielle M. Pastor 14, * and Juvianee I. Estrada-Veras 3,4,5 Academic Editor: Luca Roncucci Received: 1 October 2025 Revised: 28 November 2025 Accepted: 9 December 2025 Published: 13 December 2025 Citation: Eroglu, S.; Birsenogul, I.; Bowen, A.P.; Doyle, J.F.; Pupkin, S.E.; Villar, J.; Tarney, C.M.; Gandia, E.; Pastor, D.M.; Estrada-Veras, J.I. Lynch Syndrome in Focus: A Multidisciplinary Review of Cancer Risk, Clinical Management, and Special Populations. Cancers 2025, 17, 3981. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers17243981 Copyright: © 2025 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 ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . 1 Medical Oncology Service, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; [seyma.eroglu@nih.gov](seyma.eroglu@nih.gov) 2 Independent Researcher, Bethesda, MD 20814, USA; [ilhanbirsenogul@gmail.com](ilhanbirsenogul@gmail.com) 3 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA; [stephen.e.pupkin.ctr@health.mil](stephen.e.pupkin.ctr@health.mil) (S.E.P.); [joaquin.villar.ctr@usuhs.edu](joaquin.villar.ctr@usuhs.edu) (J.V.); [juvianee.estrada-veras.ctr@usuhs.edu](juvianee.estrada-veras.ctr@usuhs.edu) (J.I.E.-V.) 4 Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA 5 Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA 6 The Defense Health Agency, Falls Church, VA 22042, USA 7 Breast Care Center, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA 8 Center for Military Precision Health, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA 9 The American Genome Center, Bethesda, MD 20814, USA 10 Medical Corps, US Army, Fort Sam Houston, TX 78234, USA 11 Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA 12 Gynecologic Oncology, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA 13 Department of Pathology, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA 14 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA * Correspondence: [dpastor5@jh.edu](dpastor5@jh.edu) Simple Summary Lynch syndrome (LS) is the most common autosomal dominant hereditary colorectal cancer syndrome, resulting from germline pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, and deletions in EPCAM. The spectrum of tumors associated with LS is broad, and disease phenotype is quite variable, with risk of cancer development largely dependent on the involved gene. Accurate diagnosis through genetic testing and comprehensive family history assessments to identify at-risk individuals is critical to the facilitation of personalized cancer surveillance and prevention strategies. This narrative review aims to provide a comprehensive understanding of LS, from its molecular basis to current guidelines informing clinical and therapeutic practices. Abstract Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a hereditary cancer syndrome significantly increasing the risk of colorectal cancer (CRC) and various extracolonic cancers, including endometri

FAQs

What causes Lynch syndrome and which genes are involved?

Lynch syndrome results from germline pathogenic variants in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and deletions in EPCAM.

How is Lynch syndrome diagnosed in clinical practice?

Accurate diagnosis relies on genetic testing and comprehensive family history assessment. Molecular and pathology evaluation using MSI and immunohistochemistry (IHC) are highlighted as key methods.

Why does gene involvement matter for cancer risk and prevention?

The disease phenotype and cancer development risk vary by the involved gene, making gene-informed identification of at-risk individuals essential for personalized surveillance and prevention strategies.

Sep 24, 2026

Uploaded by OmBimo