Genetic Variation in Base Excision Repair Genes and the Prevalence of Advanced Colorectal Adenoma

Abstract

Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44-1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64-0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G>A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49-0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% CI, 0.33-0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1 , and PARP1 may be associated with advanced colorectal adenoma. [Cancer Res 2007;67(3):1395-404]

The C Allele of a Synonymous SNP (rs1805414, Ala284Ala) in PARP1 is a Risk Factor for Susceptibility to Breast Cancer in Saudi Patients

“…Neither variant is likely to influence the activity of the protein itself: the T allele at Ala284Ala does not affect the amino acid sequence of the protein. Thus, our results supports Berndt et al (2007) findings in which they suspected that the association that we observed with colorectal adenoma may be due to linkage disequilibrium with another variant in the region, possibly in the PARP1 promoter. Because PARP1 activity is highly regulated by its promoter, variants within transcription binding sites in the promoter may influence its expression (Berndt et al, 2007).…”

“…Thus, our results supports Berndt et al (2007) findings in which they suspected that the association that we observed with colorectal adenoma may be due to linkage disequilibrium with another variant in the region, possibly in the PARP1 promoter. Because PARP1 activity is highly regulated by its promoter, variants within transcription binding sites in the promoter may influence its expression (Berndt et al, 2007). In a similar way Milani et al (2007) reported that PARP1 contains contain functional regulatory SNPs in their promoter regions and SNP rs1805414 expression level is effected by allelic imbalance in cancer cells.…”

“…Although many studies have searched for the association between PARP-1 polymorphisms and the risk of malignancy, the results are inconsistent in different organs and in different ethnic groups. Few studies have reported positive associations between the SNP's rs1805404 and rs1805414 at position 81 and 284, have been reported to be significantly associated with an increased risk of Alzheimer's disease (Liu et al, 2010), Glioblastoma (Keller et al, 2011), protectively associated with Colorectal cancer (Berndt et al, 2007;Ogino et al, 2010). rs1805404 reported be strongly associated with Tourette syndrome risk (Wu et al, 2013).…”

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

“…The 194Trp variant has also been found to be protective against lung cancer, although it is associated with an increased risk of CRC [8]. The results for the Arg399Gln polymorphism of the XRCC1 gene in colorectal cancer epidemiology are very ambiguous [13][14][15][16][17][18].…”

Letter regarding Shen et al. entitled “The APE1 Asp148Glu polymorphism and colorectal cancer susceptibility: a meta-analysis”

“…The numbers reported by Shen et al for TT and TG/GG in controls were 70 and 52; while the numbers in Kasahara et al's original publication were 70 and 51. Also, the data reported by Shen et al for the study of Berndt et al [3] were not consistent with the data provided by Berndt et al in their original publication. The numbers reported by Shen et al for TT, TG, GG in cases and controls were 175-364-153 and 204-335-171; however, the numbers in their original publication for TT, TG, GG genotypes in cases and controls were 186-387-166 and 222-357-178, respectively.…”