Cancer risks for MSH6 pathogenic variant carriers

European Journal of Cancer, vol. 231, pp. 116098

Abstract

INTRODUCTION: Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic variants (PVs) in DNA mismatch repair genes, including MSH6. Although MSH6-associated LS (MSH6-LS) is known to increase the risk of several cancers, precise risk estimates-particularly for non-colorectal cancers-remain uncertain. This limits personalised clinical guidance for MSH6-LS. This study aims to refine cancer risk estimates for individuals with pathogenic or likely pathogenic MSH6 variants. METHODS: A retrospective cohort study was conducted using data from 360 Dutch families, comprising 1117 MSH6 PV carriers identified between 1995 and 2020. Pedigree data were collected from multiple clinical centres. Cancer diagnoses were confirmed through medical records where available. Age- and sex-specific hazard ratios (HRs) and cumulative risks (CRs) were calculated using segregation analysis, adjusted for ascertainment bias. RESULTS: By age 80, the cumulative CRC risk was 36 % for males (95 % CI: 25-48 %) and 21 % for females (95 % CI: 13-32 %). For endometrial cancer, the CR was 23 % in females (95 % CI: 15-43 %). At age 40, CRC risk remained low: 0.2 % in males and 0.9 % in females. Elevated lifetime risks were observed for ovarian cancer (6.4 %; HR 5.58), urinary tract cancers (10.1 % in males, 4.1 % in females; HR 2.52), and biliary tract cancers (4.9 % in males, 4.2 % in females; HR 2.76). No increased risk was found for prostate or breast cancer. CONCLUSION: These refined, age- and sex-specific risk estimates for MSH6 PV carriers inform tailored surveillance strategies, supporting delayed CRC screening and individualised counselling on risk-reducing surgery for women.

Authors 16

1. James G. Dowty

   The University of Melbourne

   Affiliation as printed

   Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia

2. Morrison Italia

   The University of Melbourne

   Affiliation as printed

   Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia

3. Fernande C.H.A. Koops Aachen Department of Clinical Genetics

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands

4. Fonnet E. Bleeker

   The Netherlands Cancer Institute

   Affiliation as printed

   Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, the Netherlands

5. E. Gómez

   Maastricht University Medical Centre

   Affiliation as printed

   Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands

6. Liselotte P. van Hest

   University of Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Human Genetics, Amsterdam UMC, location Vrije Universiteit Amsterdam and location University of Amsterdam, Amsterdam, the Netherlands

7. Mirjam M. de Jong

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands

8. Tom G.W. Letteboer

   University Medical Center Utrecht

   Affiliation as printed

   Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands

9. Floor A.M. Duijkers

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Human Genetics, Amsterdam UMC, Amsterdam, the Netherlands

10. Anja Wagner

    Erasmus MC · Erasmus MC Cancer Institute

    Affiliation as printed

    Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, the Netherlands

11. Ellis L. Eikenboom

    Erasmus MC · Erasmus MC Cancer Institute

    Affiliation as printed

    Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, the Netherlands

12. Christi J. van Asperen Aachen Department of Clinical Genetics

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands

13. Sanne W. ten Broeke

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands

14. Aung Ko Win

    The University of Melbourne

    Affiliation as printed

    Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia

15. Mark A. Jenkins

    The University of Melbourne

    Affiliation as printed

    Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia

16. Maartje Nielsen corresponding Aachen Department of Clinical Genetics

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands. Electronic address: m.nielsen@lumc.nl