Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

VACCARO C.A.; PIÑERO T.A.; DOMINGUEZ-VALENTIN, MEV; VACCARO C.A.; MØLLER P.; DOMINGUEZ-VALENTIN, MEV; MØLLER P.; PIÑERO T.A.

GENETICS IN MEDICINE

LIPPINCOTT WILLIAMS & WILKINS

Lugar: Philadelphia; Año: 2019

1098-3600

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, andPMS2 cause Lynch syndrome and result in different but impreciselyknown cancer risks. This study aimed to provide age and organspecificcancer risks according to gene and gender and to determinesurvival after cancer.Methods: We conducted an international, multicenter prospectiveobservational study using independent test and validation cohortsof carriers of class 4 or class 5 variants. After validation the cohortswere merged providing 6350 participants and 51,646 followupyears.Results: There were 1808 prospectively observed cancers. PathogenicMLH1 and MSH2 variants caused high penetrance dominantcancer syndromes sharing similar colorectal, endometrial, andovarian cancer risks, but older MSH2 carriers had higher risk ofcancers of the upper urinary tract, upper gastrointestinal tract,brain, and particularly prostate. Pathogenic MSH6 variants caused asex-limited trait with high endometrial cancer risk but onlymodestly increased colorectal cancer risk in both genders. We didnot demonstrate a significantly increased cancer risk in carriers ofpathogenic PMS2 variants. Ten-year crude survival was over 80%following colon, endometrial, or ovarian cancer.Conclusion: Management guidelines for Lynch syndrome mayrequire revision in light of these different gene and gender-specificrisks and the good prognosis for the most commonly associatedcancers.Keywords: Lynch syndrome; MLH1; MSH2; MSH6; PMS2