title: Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.
abstract: The MutY human homologue (MYH) gene encodes a member of the base excision repair pathway that is involved in repairing oxidative damage to DNA. Two germline MYH gene mutations that result in Myh proteins containing amino acid substitutions Y165C and G382D (hereafter called the Y165C and G382D mutations) are associated with adenomatous poly-posis and colorectal cancer among patients from several European poly-posis registries. We used a population-based series of 1238 colorectal cancer patients and 1255 healthy control subjects from Ontario, Canada, to examine the risk of colorectal cancer among biallelic and monoallelic germline MYH Y165C and G382D mutation carriers. The entire MYH gene coding region was screened in all MYH Y165C and G382D mutation carriers. Compared with noncarriers, biallelic and monoallelic germline MYH gene mutation carriers had an increased risk of colorectal cancer and were more likely to have first-or second-degree relatives with colorectal cancer (relative risk = 1.54, 95% confidence interval = 1.10 to 2.16). The increased risk of colorectal cancer in biallelic and monoallelic MYH gene mutation carriers was not consistently associated with the development of multiple adenomatous polyps. Loss of heterozygosity in at least one of four loci in MYH was detected in eight (47%) of 17 colorectal tumors from monoallelic MYH gene mutation carriers but in only two (20%) of 10 colorectal tumors from biallelic MYH gene mutation carriers. These two MYH gene mutations may account for a substantial fraction of hereditary colorectal cancer.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Croitoru
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cleary
authors.forename: Nando
authors.initials: N
authors.lastname: Di Nicola
authors.forename: Michael
authors.initials: M
authors.lastname: Manno
authors.forename: Teresa
authors.initials: T
authors.lastname: Selander
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.forename: Mark
authors.initials: M
authors.lastname: Redston
authors.forename: Michelle
authors.initials: M
authors.lastname: Cotterchio
authors.forename: Julia
authors.initials: J
authors.lastname: Knight
authors.forename: Robert
authors.initials: R
authors.lastname: Gryfe
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D001224:Aspartic Acid; D020137:Base Pair Mismatch; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D003545:Cysteine; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D005998:Glycine; D006801:Humans; D019656:Loss of Heterozygosity; D009864:Ontario / Q000453:epidemiology; D010641:Phenotype; D012307:Risk Factors; D014443:Tyrosine
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D001224:Aspartic Acid; D014443:Tyrosine; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D003545:Cysteine; D005998:Glycine