Elsevier

European Journal of Cancer

Volume 46, Issue 13, September 2010, Pages 2457-2466
European Journal of Cancer

Polymorphisms in the adenomatous polyposis coli (APC) gene and advanced colorectal adenoma risk

https://doi.org/10.1016/j.ejca.2010.04.020Get rights and content

Abstract

While germline mutations in the adenomatous polyposis coli (APC) gene cause the hereditary colon cancer syndrome (familial adenomatous polyposis (FAP)), the role of common germline APC variants in sporadic adenomatous polyposis remains unclear. We studied the association of eight APC single nucleotide polymorphisms (SNPs), possibly associated with functional consequences, and previously identified gene–environment (dietary fat intake and hormone replacement therapy (HRT) use) interactions, in relation to advanced colorectal adenoma in 758 cases and 767 sex- and race-matched controls, randomly selected from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma of the distal colon; controls, a negative sigmoidoscopy. We did not observe an association between genotypes for any of the eight APC SNPs and advanced distal adenoma risk (Pglobal gene-based = 0.92). Frequencies of identified common haplotypes did not differ between cases and controls (Pglobal haplotype test = 0.97). However, the risk for advanced distal adenoma was threefold higher for one rare haplotype (cases: 2.7%; controls: 1.6%) (odds ratio (OR) = 3.27; 95% confidence interval (CI) = 1.08–9.88). The genetic association between D1822V and advanced distal adenoma was confined to persons consuming a high-fat diet (Pinteraction = 0.03). Similar interactions were not observed with HRT use. In our large, nested case-control study of advanced distal adenoma and clinically verified adenoma-free controls, we observed no association between specific APC SNPs and advanced adenoma. Fat intake modified the APC D1822V-adenoma association, but further studies are warranted.

Section snippets

Background

Colorectal cancer (CRC) is the leading cause of cancer-related death, second only to lung cancer in developed countries.1, 2 Though fewer than 10% of colorectal adenomas are thought to progress to adenocarcinomas,3 more than 70% of colonic carcinomas are thought to arise within pre-existing sporadic precursors of malignant lesions, adenomatous polyp (adenoma), of the colorectal epithelium.4 Advanced adenoma, associated with the greatest increased risk of CRC, is characterised as large (>1 cm)

Materials and methods

This case-control study was nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which was designed to evaluate selected methods for the early detection of these cancers and to investigate aetiologic factors and early markers of cancer.53, 54 Participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, ages 55–74 years, were recruited at 10 centres in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI;

Results

In our nested case-control study from the PLCO cohort (previously described61), cases with advanced distal adenoma tend to be older, less educated, smoke more, have a family history of CRC and consume less folate and calcium (Table 1). The minor allele frequencies of the eight APC SNPs ranged from 2.2% to 48.4% among the non-Hispanic Whites that comprised 94% of the cases and controls (Table 2).

We examined the association between each of the APC SNPs on advanced distal adenoma risk (Table 3).

Discussion

In the largest study to date of APC common variants and advanced colorectal adenoma risk, our single locus and haplotype data do not support the role of common polymorphisms in APC in colorectal development. No statistically significant associations were observed between any of the eight APC SNPs examined and advanced distal adenomas. One rare ‘at-risk’ haplotype was over-represented in advanced distal adenoma cases as compared to controls (2.7% in cases versus 1.6% in controls), no other

Conflict of interest statement

None declared.

Acknowledgements

This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organisations imply endorsement by the US Government.

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