Nature Genetics30, 227 - 232 (2002)
Published online: 30 January 2002; | doi:10.1038/ng828
Inherited variants of MYH associated with somatic G:CT:A mutations in colorectal tumors
Nada Al-Tassan1, Nikolas H. Chmiel2, Julie Maynard1, Nick Fleming1, Alison L. Livingston2, Geraint T. Williams3, Angela K. Hodges1, D. Rhodri Davies4, Sheila S. David2, Julian R. Sampson1
& Jeremy P. Cheadle1
1
Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
2
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
3
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
4
Department of Gastroenterology, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK.
Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A1,
2,
3,
4. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis5. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:CT:A transversions—a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH6, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity7. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans.
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T:A mutations in colorectal tumors
