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Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors


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:C→T: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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Figure 1: Pedigree of family N.
Figure 2: Identification of somatic G:C→T:A mutations of APC in colorectal tumors from family N.
Figure 3: Identification and segregation of germline MYH variants in family N.
Figure 4: Evolutionary conservation of the variant residues in MYH.
Figure 5: Representative plots of single-turnover adenine glycosylase assays.

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We thank A. Wilkie, I. Frayling and R. Snell for advice; I. Tomlinson for advice and primers for exons 1–3 and 5–14 of APC; M.M. Slupska for genomic sequence spanning the MYH locus; M. Krawczak for statistical assistance; J. Best, J. Myring, S. Palmer-Smith, M. McDonald, L. Parry, A. Radcliffe, N. Dallimore and C. Simpson for help with sample collection and preparation; P. Davies for help with dHPLC analysis; and S. Owen and D.S. Jackson for clinical assistance. This work was supported by grants from the King Saud University through the Saudi Cultural Bureau, Tenovus, and from the National Institutes of Health. S.S.D. is an A.P. Sloan research fellow and A.L.L. is an NIH predoctoral trainee.

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Correspondence to Julian R. Sampson.

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Al-Tassan, N., Chmiel, N., Maynard, J. et al. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat Genet 30, 227–232 (2002).

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