Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers.
MYH-associated polyposis is a recently described, autosomal recessive condition comprising multiple colorectal adenomas and cancer. This disease is caused by germline mutations in the base excision repair (BER) gene MYH. Genes involved in the BER pathway are thus good candidates for involvement in the pathogenesis of sporadic tumors of the large bowel. We have screened a set of 75 sporadic colorectal cancers for mutations in MYH, MTH1, and OGG1. Allelic loss at MYH was also assessed. Selected samples were screened for mutations and allele loss at APC and mutations in p53, K-ras, and beta-catenin. A panel of 35 colorectal cancer cell lines was screened for MYH mRNA and protein expression. One of 75 cancers had bi-allelic germline mutations in MYH and on retrospective analysis of medical records this patient was found to have synchronous multiple small adenomas in addition to carcinoma. No somatic MYH mutations were found and mRNA and protein were expressed in all of our cell lines. There were no clearly pathogenic mutations in MTH1 or OGG1 in any tumor. Bi-allelic germline MYH mutations cause approximately 1 to 3% of unselected colorectal cancers, but appear always to be associated with multiple adenomas. Somatic inactivation of the DNA glycosylases involved in the BER pathway however does not appear to be involved in colorectal tumorigenesis.
Halford
Sarah E R
SE
Molecular and Population Genetics Laboratory, London Institute, Cancer Research United Kingdom, London, UK.
Rowan
Andrew J
AJ
Lipton
Lara
L
Sieber
Oliver M
OM
Pack
Kevin
K
Thomas
Huw J W
HJ
Hodgson
Shirley V
SV
Bodmer
Walter F
WF
Tomlinson
Ian P M
IP
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology; D001483:Base Sequence; D003082:Colectomy; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D045647:DNA Glycosylases; D017931:DNA Primers; D017353:Gene Deletion; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D009699:N-Glycosyl Hydrolases / Q000235:genetics*
D017931:DNA Primers; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C061738:mutY adenine glycosylase