Cancer Risks Associated With Germline Mutations in <emph type="ital">MLH1</emph>, <emph type="ital">MSH2</emph>, and <emph type="ital">MSH6</emph> Genes in Lynch Syndrome

TLDR

Accurate cancer risk estimation remains a major challenge in Lynch syndrome management. This study aimed to estimate age‑specific cumulative risks for colorectal, endometrial, ovarian, and other tumors in carriers of MLH1, MSH2, and MSH6 mutations. Using genotype‑restricted likelihood analysis on 537 families from 40 French clinics (2006‑2009) while accounting for ascertainment bias, the authors derived cumulative risks. The analysis revealed markedly lower lifetime risks for MSH6 carriers (colorectal 12 %, endometrial 16 %, ovarian 1 %) compared to MLH1 (41 %, 54 %, 20 %) and MSH2 (48 %, 21 %, 24 %) carriers, with significant gene‑specific differences (P = 0.01) and high MLH1/MSH2 risks only rising after age 40.

Abstract

Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome.To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes.Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed.Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias.Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations.MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.