DOI: 10.1097/DCR.0b013e31823a9392
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PMID: 22469805
Issn Print: 0012-3706
Publication Date: 2012/03/01
Understanding MYH-Associated Neoplasia
James Church; Brandie Heald; Carol Burke; Matt Kalady
Excerpt
In 2002, a group of molecular geneticists from Cardiff in Wales reported a new, inherited syndrome of colorectal cancer predisposition. The group had studied a family in which 2 siblings were affected by approximately 50 colorectal adenomas each, and a third had died of colorectal cancer. Genetic testing excluded a primary inherited defect of APC. However, when DNA from 11 adenomas was analyzed for somatic abnormalities in APC, 18 inactivating mutations were found. Importantly, 15 of the 18 were G:C to T:A transversions, mutations that result from DNA oxidation. The group then sequenced the genes responsible for repair of oxidative damage to DNA, those involved in base excision repair. There are 3 such genes: MYH, OGG1, and MTH. They found that all 3 affected siblings were compound heterozygotes for mutations Tyr165Cys and Gly382Asp in MYH. There were no mutations in the other 2 genes. Other relatives were either normal, or heterozygous for one of the mutations.1 Other work confirmed these findings and the role of biallelic mutations in MYH in producing recessively inherited familial adenomatous polyposis was established.2,3 The syndrome became known as MYH-associated polyposis (MAP). Its discovery has opened new fields of research and provided another genetic mechanism for mild polyposis in APC mutation-negative families. However, over the 9 years since the initial description of MYH and the polyposis associated with it, the accumulating literature has shown that MYH-associated neoplasia is neither simple nor straightforward.4 Biallelic MYH mutations do not always cause adenomatous polyposis. Other syndromes of hereditary colorectal cancer may be mimicked, and there may even be no hint at all of hereditary risk when MYH mutations give rise to apparently sporadic colorectal cancers. The purpose of this review is to highlight the phenotypic heterogeneity associated with biallelic MYH mutations and its impact on diagnosis and clinical care.
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