Incident Cancer Risk and Signatures Among Older MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts.

Jonathan M Downie, Moeen Riaz, Jing Xie, Minyi Lee, Andrew T Chan, Peter Gibbs, Suzanne G Orchard, Suzanne E Mahady, Robert P Sebra, Anne M Murray, Finlay Macrae, Eric Schadt, Robyn L Woods, John J McNeil, Paul Lacaze, Manish Gala

MUTYH carriers have an increased colorectal cancer (CRC) risk in case-control studies, with loss of heterozygosity (LOH) as the presumed mechanism. We evaluated cancer risk among carriers in a prospective, population-based cohort of older adults. Additionally, we assessed if cancers from carriers demonstrated mutational signatures (G:C>T:A transversions) associated with early LOH. We calculated incident risk of cancer and CRC among 13,131 sequenced study participants of the ASPirin in Reducing Events in the Elderly (ASPREE) cohort, stratified by sex and adjusting for age, smoking, alcohol use, BMI, polyp history, history of cancer, and aspirin use. MUTYH carriers were identified among 13,033 participants in The Cancer Genome Atlas and International Cancer Genome Consortium, and somatic signatures of cancers were analyzed. Male MUTYH carriers demonstrated an increased risk for overall cancer incidence (multivariable HR 1.66, 95% CI [1.03, 2.68]; P = 0.038) driven by increased CRC incidence (multivariable HR 3.55, 95% CI [1.42, 8.78]; P = 0.007), as opposed to extracolonic cancer incidence (multivariable HR 1.40, 95% CI [0.81, 2.44]; P = 0.229). Female carriers did not demonstrate increased risk of cancer, CRC, or extracolonic cancers. Analysis of mutation signatures from cancers of MUTYH carriers revealed no significant contribution toward early mutagenesis from widespread G:C>T:A transversions among gastrointestinal epithelial cancers. Among cancers from carriers, somatic transversions associated with base-excision repair deficiency are uncommon, suggestive of diverse mechanisms of carcinogenesis in carriers compared to those who inherit biallelic MUTYH mutations.