Abstract B85: Genetic variation in the base excision repair pathway, environmental risk factors and colorectal adenoma risk
Authors: Corral Roman , Lewinger Juan Pablo , Joshi Amit D. , Levine A. Joan , Berg David Van Den , Haile Robert W. , Stern Mariana C. 
Published: January 2014

Background: Three inter-related and consistent factors emerging from the epidemiological literature for colorectal adenoma are cigarette smoking, alcohol intake, and dietary folate levels. Oxidative damage caused by these three factors can be repaired through the base excision repair pathway (BER). The ability to repair such damage may be modified by common genetic variants in BER pathway genes. In a sigmoidoscopy based study, we examined associations between 182 haplotype tagging single nucleotide polymorphisms (SNPs), which captured common genetic variation in 14 BER genes, and colorectal adenoma risk. Additionally, the interaction effects between SNPs and cigarette smoking, alcohol intake, and dietary folate levels were examined.

Methods: We used data and samples from 721 cases and 736 controls enrolled in a University of Southern California/Kaiser Permanente sigmoidoscopy-based study of risk factors for colorectal adenomas. Genotype data on 182 haplotype tagging SNPs were obtained using the Golden Gate Assay (Illumina, Inc). Using logistic regression, per allele odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between SNPs and colorectal adenoma risk. Using multinomial logistic regression, per allele ORs and 95% CIs for each SNP were calculated after stratifying on adenoma location (rectal versus left colon) and adenoma size (&lt; 1 cm versus ≥ 1cm). Adenoma, adenoma location and adenoma size associations were corrected for multiple testing for all SNPs within each gene using the multiple testing correction method implemented in the R package PACT, and additionally for the 14 different genes within the BER pathway using the Bonferroni method. Interaction effects between SNPs and smoking, alcohol and dietary folate intake on colorectal adenoma risk were tested using logistic regression models and corrected for within each gene and additionally for the 14 different genes within the BER pathway using the Bonferroni method.

Results: Among African-Americans we observed an increased risk of adenoma with APEX1 rs17111750 (OR = 2.19; 95%CI = 1.36-3.55; pACT = 0.013). Among Asian-Pacific Islanders we observed an increased risk of adenoma with FEN1 rs108499 (OR = 2.12; 95%CI = 1.30-3.45; pACT = 0.009). Among the entire study population, an increased risk of rectal adenoma was observed for two unlinked SNPs in the NEIL2 gene: NEIL2 rs7015453 (OR = 1.72; 95%CI = 1.24-2.39; pACT =0.025) and rs3757949 (OR=1.58; 95%CI= 1.18-2.13; pACT = 0.044). Both NEIL2 SNPs showed evidence of statistically significant heterogeneity of the ORs by adenoma location (rs7015453, p = 0.003; rs3757949, p = 0.004). The association between smoking (pack-years) and adenoma risk was modified by MUTYH rs10890324 (interaction pgene = 0.009). The association between alcohol intake and adenoma risk was modified by LIG3 rs1052536 (interaction pgene = 0.028). The association between dietary folate intake and adenoma risk was modified by two unlinked LIG3 SNPs (rs1052536 interaction pgene = 0.009; rs3744358 interaction pgene = 0.048) and one XRCC1 SNP (rs3213344 interaction pgene = 0.046).

Conclusions: The findings support our hypothesis that genetic variation in DNA repair genes can modify the association of key colorectal adenoma risk factors. Our findings support a role for oxidative damage induced by these exposures on colorectal cancer formation.

Citation Format: Roman Corral, Juan Pablo Lewinger, Amit D. Joshi, A. Joan Levine, David Van Den Berg, Robert W. Haile, Mariana C. Stern. Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B85.