Oncology
Whether monoallelic MUTYH mutation carriers are at increased risk of breast cancer (BC) and/or colorectal cancer (CRC) remains controversial. We aimed to determine whether monoallelic MUTYH mutations are associated with increased BC and/or CRC risk by comparing the frequency of MUTYH mutations among BC and CRC cases to controls from a multi-gene panel testing (MGPT) cohort.
Cases included Caucasian individuals with female BC (N=16,921; 349 MUTYH carriers) or CRC (N=2,582; 60 MUTYH carriers) who had MGPT including MUTYH at a clinical diagnostic laboratory. Control cohorts for the BC (N=10,879; 240 MUTYH carriers) and CRC (N=27,514; 577 MUTYH carriers) comparisons included Caucasian individuals who had MGPT including MUTYH at the same laboratory without personal history of BC or CRC, respectively. The frequency of all MUTYH mutations was compared between each of the case cohorts and the respective control cohort. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were also assessed independently as well as combined. Odds ratios (OR) were obtained from logistic regression analyses after adjusting for covariates.
No association was found between female BC and carrier status of any MUTYH mutation (OR=1.0), p.G396D alone (OR=0.9), p.Y179C alone (OR=0.9) or both founder mutations combined (OR=0.9) after controlling for personal and family history of CRC and carrier status of mutations in other genes. Similarly, no association was found between CRC and carrier status of any MUTYH mutation (OR=1.1), p.G396D alone (OR=1.2), p.Y179C alone (OR=0.7) or both founder mutations combined (OR=1.1) after controlling for personal and family history of female BC and carrier status of mutations in other genes.
In summary, these data do not support a significant association of BC or CRC risk with monoallelic MUTYH carrier status. To our knowledge, this is the largest cohort used to assess the association of BC risk with MUTYH monoallelic mutations and the first study to assess cancer association in MUTYH carriers identified on MGPT. Additional studies that include larger numbers of MUTYH mutation carriers, in addition to having larger CRC cohorts, are needed to confirm these results. Future studies should also evaluate whether MUTYH carriers are at increased risk for other cancers, such as gastric, liver and endometrial, given the recent literature supporting this