Cancer risks for MSH6 pathogenic variant carriers

medRxiv

Abstract

Abstract Introduction Lynch syndrome (LS) is a hereditary cancer syndrome caused by (likely) pathogenic variants (LP/P) in DNA mismatch repair genes, including MSH6 . It is associated with elevated lifetime risks for colorectal cancer (CRC), endometrial cancer (EC), and other malignancies. However, cancer risks specific to MSH6 -associated LS, particularly for non-colorectal cancers, remain poorly defined. This study aims to provide refined cancer risk estimates for individuals with MSH6 LP/P. Methods We conducted a retrospective cohort study of 360 families with 1117 known MSH6 LP/P carriers identified in the Netherlands between 1995 and 2020. Pedigree data were collected from multiple clinical centers, and cancer diagnoses were confirmed through medical records. Age- and sex-specific hazard ratios (HRs) and cumulative risks (CRs) were estimated using segregation analysis, appropriately adjusted for ascertainment. Results CR by age 80 for MSH6 LP/P carriers were 36% in males (95% CI:25–48%) and 21% in females (95% CI 13–32%) for CRC, and 23% in females (95% CI:15–43%) for EC. Elevated risks were observed for ovarian cancer (OC) (6.4%, 95% CI:3–14.8%; HR 5.58, p=0.00037), urinary tract cancers (10.1% in males, 4.1% in females; HR 2.52, p=0.012), and biliary tract cancers (4.9% in males, 4.2% in females; HR 2.76, p=0.031). No increased risks were identified for prostate or breast cancer. Conclusion This study refines cancer risk estimates for MSH6 LP/P carriers, suggesting the need for delayed CRC screening in males and females and proactive discussions regarding prophylactic surgery for females to address elevated risks for EC and OC.

Authors 15

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. F.B.J. Koops Aachen

   Leiden University Medical Center

   Affiliation as printed

   LUMC;

4. Fonnet E. Bleeker
   Affiliation as printed

   AvL;

5. E. Gómez

   Maastricht University Medical Centre · Maastricht University

   Affiliation as printed

   Department of Clinical Genetics , Maastricht University Medical Center , Maastricht , The Netherlands

6. Liselotte P. van Hest

   Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Human Genetics , Amsterdam UMC , location Vrije Universiteit Amsterdam and

7. Tom G.W. Letteboer

   University Medical Center Utrecht

   Affiliation as printed

   UMCU;

8. Floor A.M. Duijkers
   Affiliation as printed

   AUMC;

9. Anja Wagner

   Erasmus MC

   Affiliation as printed

   ErasmusMC;

10. Ellis L. Eikenboom

    Erasmus MC

    Affiliation as printed

    ErasmusMC;

11. Christi J. van Asperen Aachen

    Leiden University Medical Center

    Affiliation as printed

    LUMC;

12. Sanne W. ten Broeke

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Genetics , University Medical Center Groningen , University of Groningen , Groningen , The Netherlands

13. Aung Ko Win

    The University of Melbourne

    Affiliation as printed

    Melbourne University

14. Mark Jenkins

    The University of Melbourne

    Affiliation as printed

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

15. Maartje Nielsen corresponding Aachen

    Leiden University Medical Center

    Affiliation as printed

    LUMC;