Presence of a TA Haplotype in the APC Gene Containing the Common 1822 Polymorphism and Colorectal Adenoma

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. [Cancer Res 2008;68(14):6006-13]

Risk factors for metachronous colorectal cancer or polyp: A systematic review and meta‐analysis

“…A manual search of reference lists captured nine further studies that met our entry criteria . Thus, 55 studies published between 1987 and 2016 were included in the review (Tables and ) …”

“…The majority of the other studies excluded high‐risk people including those with Lynch syndrome or familial adenomatous polyposis and inflammatory bowel disease. The studies that included only high‐risk people, studies that did not define the disease‐free interval between the initial and metachronous colorectal neoplasia (which included the three case–control studies) or defined an interval less than 6 months, and small studies that were conducted using a sample size of less than 50 participants were not used to derive pooled risk estimates but were reviewed narratively.…”

“…Only one study investigated the association between single nucleotide polymorphisms and the incidence of metachronous colorectal adenoma . Egan et al .…”

APC Yin-Yang haplotype associated with colorectal cancer risk

“…many of them analyzed separate SnPs (16)(17)(18)(19)(20), while a few others analyzed the combination of various SnPs (haplotypes) (21,22). However, no studies have been published involving diplotype structure and colon cancer risk.…”

Assinatura de mRNA entre adenoma e adenocarcinoma colorretal

“…Diversos trabalhos observaram uma alta frequência de alterações no gene APC (Miyoshi et al, 1992;Rowan et al, 2000;Egan et al, 2008), mas em contraste, não encontramos nenhuma mutação somática no APC, apesar do alto número de polimorfismos germinativos o que poderia ser explicado pelo pequeno número de amostras (10). Além disso, de acordo com Guerreiro et al…”