Increased Colorectal Cancer Incidence in Obligate Carriers of Heterozygous Mutations in MUTYH

Background & Aims MUTYH-associated polyposis (MAP) is an autosomal recessive disorder caused by mutations in the MUTYH gene. Patients with MAP are at extremely high risk of colorectal cancer, but the risks of colorectal and other cancers in heterozygous carriers of a single MUTYH mutation are uncertain. We performed a retrospective study of cancer incidence and causes of death among obligate MUTYH heterozygote individuals. Methods MAP index cases were identified from polyposis registers in Germany, The Netherlands, and the United Kingdom. Cancer incidence, cancer mortality, and all-cause mortality data were collected from 347 parents of unrelated MAP index cases and the spouses of 3 index cases who were also found to be heterozygous for single MUTYH mutations. These data were compared with appropriate national sex-, age-, and period-specific population data to obtain standardized mortality ratios (SMR) and standardized incidence ratios (SIR). Results There was a 2-fold increase in the incidence of colorectal cancer among parents of MAP cases, compared with the general population (SIR, 2.12; 95% confidence interval [CI]: 1.30–3.28). Their colorectal cancer mortality was not increased significantly (SMR, 1.02; 95% CI: 0.41–2.10) nor was overall cancer risk (SIR, 0.92; 95% CI: 0.70–1.18), cancer mortality (SMR, 1.12; 95% CI: 0.83–1.48), or overall mortality (SMR, 0.94; 95% CI: 0.80–1.08). Conclusions The risk of colorectal cancer in heterozygous carriers of single MUTYH mutations who are relatives of patients with MAP is comparable with that of first-degree relatives of patients with sporadic colorectal cancer. Screening measures should be based on this modest increase in risk.