Missense polymorphisms in the adenomatous polyposis coli gene and colorectal cancer risk.
OBJECTIVE
Whereas truncating germline mutations of the adenomatous polyposis coli (APC) gene give rise to familial adenomatous polyposis, missense polymorphisms of APC may confer a weaker risk for colorectal cancer.


METHODS
We sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas. Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects.


RESULTS
Germline APC or mutY human homologue (MYH) alterations were identified in 16 of 39 colorectal cancer-multiple polyp patients. Four missense APC gene alterations (S130G, E1317Q, D1822V, G2502S) were observed in 13 individuals and 3 additional patients carried presumed pathogenic (APC Y94X, biallelic MYH Y165C and heterozygous MYH G382D) mutations. When independently assessed in 971 patients with colorectal cancer and 954 healthy control subjects, none of the identified missense APC alterations conferred a significantly increased risk for colorectal cancer, odds ratio (95 percent confidence intervals): S130G = 3.1 (0.29-32.25), E1317Q = 1.08 (0.59-2.74), G2502S = 1 (0.65-1.63), D1822V (heterozygous) = 0.79 (0.64-0.98), D1822V (homozygous) = 0.82 (0.63-1.27).


CONCLUSIONS
Germline missense APC alterations observed in 33 percent of patients with multiple colorectal neoplasms seemed to play a limited role in colorectal cancer risk when independently assessed by a population-based, case-control analysis.
Cleary
Sean P
SP
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Kim
Hyeja
H
Croitoru
Marina E
ME
Redston
Mark
M
Knight
Julia A
JA
Gallinger
Steven
S
Gryfe
Robert
R
D011125:Adenomatous Polyposis Coli / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D017491:Genes, APC; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009864:Ontario / Q000453:epidemiology; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors; D018709:Statistics, Nonparametric; D011795:Surveys and Questionnaires