Increased mutation frequency among Dutch families with breast cancer and colorectal cancer

Homozygous and compound heterozygous mutations predispose for MUTYH-associated polyposis (MAP). The clinical phenotype of MAP is characterised by the multiple colorectal adenomas and colorectal carcinoma. We previously found that female MAP patients may also have an increased risk for breast cancer. Yet, the involvement of mutations in families with both breast cancer and colorectal cancer is unclear. Here, we have genotyped the p.Tyr179Cys, p.Gly396Asp and p.Pro405Leu founder mutations in 153 Dutch families with breast cancer patients and colorectal cancer patients. Families were classified as polyposis, revised Amsterdam criteria positive (FCRC-AMS positive), revised Amsterdam criteria negative (FCRC-AMS negative), hereditary breast and colorectal cancer (HBCC) and non-HBCC breast cancer families. As anticipated, biallelic mutations were identified among 13% of 15 polyposis families, which was significantly increased compared to the absence of biallelic mutations in the population ( = 0.0001). Importantly, six heterozygous mutations were identified among non-polyposis families with breast and colorectal cancer. These mutations were identified specifically in FCRC-AMS negative and in HBCC breast cancer families (11% of 28 families and 4% of 74 families, respectively; = 0.02 for both groups combined vs. controls). Importantly, the 11% frequency among FCRC-AMS negative families was almost fivefold higher than the reported frequencies for FCRC-AMS negative families unselected for the presence of breast cancer patients ( = 0.03). Together, our results indicate that heterozygous mutations are associated with families that include both breast cancer patients and colorectal cancer patients, independent of which tumour type is more prevalent in the family.