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

Nada Al-Tassan, Nikolas H. Chmiel, Julie Maynard, Nick Fleming, Alison L. Livingston, Geraint T. Williams, Angela K. Hodges, D. Rhodri Davies, Sheila S. David, Julian R. Sampson, Jeremy P. Cheadle

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Abstract

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:A1-4. 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.

Original languageEnglish (US)
Pages (from-to)227-232
Number of pages6
JournalNature Genetics
Volume30
Issue number2
DOIs
StatePublished - Feb 2002
Externally publishedYes

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Colorectal Neoplasms
APC Genes
Mutation
DNA Repair
Neoplasms
Escherichia coli
Inborn Genetic Diseases
Adenomatous Polyposis Coli
Medical Genetics
Mutant Proteins
Heterozygote
Adenoma
Tyrosine
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Al-Tassan, N., Chmiel, N. H., Maynard, J., Fleming, N., Livingston, A. L., Williams, G. T., ... Cheadle, J. P. (2002). Inherited variants of MYH associated with somatic G: C→T:A mutations in colorectal tumors. Nature Genetics, 30(2), 227-232. https://doi.org/10.1038/ng828

Inherited variants of MYH associated with somatic G : C→T:A mutations in colorectal tumors. / Al-Tassan, Nada; Chmiel, Nikolas H.; Maynard, Julie; Fleming, Nick; Livingston, Alison L.; Williams, Geraint T.; Hodges, Angela K.; Davies, D. Rhodri; David, Sheila S.; Sampson, Julian R.; Cheadle, Jeremy P.

In: Nature Genetics, Vol. 30, No. 2, 02.2002, p. 227-232.

Research output: Contribution to journalArticle

Al-Tassan, N, Chmiel, NH, Maynard, J, Fleming, N, Livingston, AL, Williams, GT, Hodges, AK, Davies, DR, David, SS, Sampson, JR & Cheadle, JP 2002, 'Inherited variants of MYH associated with somatic G: C→T:A mutations in colorectal tumors', Nature Genetics, vol. 30, no. 2, pp. 227-232. https://doi.org/10.1038/ng828
Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT et al. Inherited variants of MYH associated with somatic G: C→T:A mutations in colorectal tumors. Nature Genetics. 2002 Feb;30(2):227-232. https://doi.org/10.1038/ng828
Al-Tassan, Nada ; Chmiel, Nikolas H. ; Maynard, Julie ; Fleming, Nick ; Livingston, Alison L. ; Williams, Geraint T. ; Hodges, Angela K. ; Davies, D. Rhodri ; David, Sheila S. ; Sampson, Julian R. ; Cheadle, Jeremy P. / Inherited variants of MYH associated with somatic G : C→T:A mutations in colorectal tumors. In: Nature Genetics. 2002 ; Vol. 30, No. 2. pp. 227-232.
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