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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 &gt;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--&gt;T:A mutations in APC, as compared to sporadic ( chi(2)=242.96, P&lt;10(-20)) or FAP-associated ( chi(2)=194.85, P&lt;10(-20)) colorectal tumours. The sequence immediately downstream of the somatic G:C--&gt;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.

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