Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C→T:A mutations

We have recently demonstrated that inherited defects of the base excision repair gene MYH predispose to multiple colorectal adenomas and carcinoma. Three affected siblings from a single British family were identified as Y165C/G382D compound heterozygotes and both missense mutations were shown to be functionally compromised. Here, we report the identification of seven further unrelated patients with >100 colorectal adenomas (six with colorectal cancer) and biallelic germline mutations in MYH: four were homozygous for truncating mutations, two were homozygous for Y165C and one was a Y165C/G382D compound heterozygote. As predicted from studies of the bacterial and yeast orthologues of MYH, colorectal tumours from affected individuals displayed a significant excess of somatic G:C→T:A mutations in APC, as compared to sporadic (X² = 242.96, P< 10^-20) or FAP-associated (X² = 194.85, P< 10^-20) colorectal tumours. The sequence immediately downstream of the somatic G:C→T:A mutations was predominantly AA, irrespective of the nature of the germline MYH mutations. These findings confirm the role of MYH in colorectal adenoma and carcinoma predisposition.