Presence of a TA haplotype in the APC gene containing the common 1822 polymorphism and colorectal adenoma

Jan B. Egan, Elizabeth T Jacobs, María Elena Martínez, Eugene W. Gerner, Peter W. Jurutka, Patricia A. Thompson

Research output: Contribution to journalArticle

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Abstract

Acquired or inherited mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are causally linked to colorectal cancer. Given the significance of APC in colorectal cancer, we investigated the association between common single-nucleotide polymorphisms (SNP) in the APC gene and the odds of developing metachronous colorectal adenomas as a surrogate measure of colorectal cancer risk. Coding SNPs at codons 486, 1678, 1822, 1960, and 2502 were analyzed in a total of 1,399 subjects who participated in two randomized clinical trials for the prevention of colorectal adenomas. No association was found for any single SNP and the odds of metachronous adenoma. In contrast, a TA haplotype (codons 486 and 1822) was associated with a statistically significant 27% and 26% reduction in the odds of any and nonadvanced metachronous adenoma after adjustment for baseline adenoma characteristics [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.59-0.91 and OR, 0.74; 95% CI, 0.57-0.94], respectively. No significant reduction in odds was observed for advanced metachronous lesions. Diplotype analysis revealed a strong gene dose effect with carriers of two alleles containing TT-AA (codons 486 and 1822, respectively) having an 89% lower odds for advanced metachronous adenomas (OR, 0.11; 95% CI, 0.01-0.80) when compared with the common CC-AA diplotype (codons 486 and 1822, respectively). Our findings support an important role for germ-line allele sequence in the APC gene and individual risk of metachronous adenomatous polyps.

Original languageEnglish (US)
Pages (from-to)6006-6013
Number of pages8
JournalCancer Research
Volume68
Issue number14
DOIs
StatePublished - Jul 15 2008

Fingerprint

APC Genes
Adenoma
Haplotypes
Codon
Single Nucleotide Polymorphism
Colorectal Neoplasms
Adenomatous Polyposis Coli
Odds Ratio
Confidence Intervals
Alleles
Adenomatous Polyps
Tumor Suppressor Genes
Germ Cells
Randomized Controlled Trials
Mutation
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Presence of a TA haplotype in the APC gene containing the common 1822 polymorphism and colorectal adenoma. / Egan, Jan B.; Jacobs, Elizabeth T; Martínez, María Elena; Gerner, Eugene W.; Jurutka, Peter W.; Thompson, Patricia A.

In: Cancer Research, Vol. 68, No. 14, 15.07.2008, p. 6006-6013.

Research output: Contribution to journalArticle

Egan, Jan B. ; Jacobs, Elizabeth T ; Martínez, María Elena ; Gerner, Eugene W. ; Jurutka, Peter W. ; Thompson, Patricia A. / Presence of a TA haplotype in the APC gene containing the common 1822 polymorphism and colorectal adenoma. In: Cancer Research. 2008 ; Vol. 68, No. 14. pp. 6006-6013.
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abstract = "Acquired or inherited mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are causally linked to colorectal cancer. Given the significance of APC in colorectal cancer, we investigated the association between common single-nucleotide polymorphisms (SNP) in the APC gene and the odds of developing metachronous colorectal adenomas as a surrogate measure of colorectal cancer risk. Coding SNPs at codons 486, 1678, 1822, 1960, and 2502 were analyzed in a total of 1,399 subjects who participated in two randomized clinical trials for the prevention of colorectal adenomas. No association was found for any single SNP and the odds of metachronous adenoma. In contrast, a TA haplotype (codons 486 and 1822) was associated with a statistically significant 27{\%} and 26{\%} reduction in the odds of any and nonadvanced metachronous adenoma after adjustment for baseline adenoma characteristics [odds ratio (OR), 0.73; 95{\%} confidence interval (95{\%} CI), 0.59-0.91 and OR, 0.74; 95{\%} CI, 0.57-0.94], respectively. No significant reduction in odds was observed for advanced metachronous lesions. Diplotype analysis revealed a strong gene dose effect with carriers of two alleles containing TT-AA (codons 486 and 1822, respectively) having an 89{\%} lower odds for advanced metachronous adenomas (OR, 0.11; 95{\%} CI, 0.01-0.80) when compared with the common CC-AA diplotype (codons 486 and 1822, respectively). Our findings support an important role for germ-line allele sequence in the APC gene and individual risk of metachronous adenomatous polyps.",
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