Nucleotide excision repair gene polymorphisms, meat intake and colon cancer risk

Highlights

• We examined DNA repair gene polymorphisms, red meat intake, and colon cancer risk.

• Main effects of seven SNPs and interactions with diet were examined by race.

• Two SNPs were associated with risk of colon cancer among African Americans.

• High meat carcinogen intake and presence of >3 at-risk alleles jointly increased risk.

Abstract

Purpose

Much of the DNA damage from colon cancer-related carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH) from red meat cooked at high temperature, are repaired by the nucleotide excision repair (NER) pathway. Thus, we examined whether NER non-synonymous single nucleotide polymorphisms (nsSNPs) modified the association between red meat intake and colon cancer risk.

Methods

The study consists of 244 African-American and 311 white colon cancer cases and population-based controls (331 African Americans and 544 whites) recruited from 33 counties in North Carolina from 1996 to 2000. Information collected by food frequency questionnaire on meat intake and preparation methods were used to estimate HCA and benzo(a)pyrene (BaP, a PAH) intake. We tested 7 nsSNPs in 5 NER genes: XPC A499V and K939Q, XPD D312N and K751Q, XPF R415Q, XPG D1104H, and RAD23B A249V. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression.

Results

Among African Americans, we observed a statistically significant positive association between colon cancer risk and XPC 499 AV+VV genotype (OR = 1.7, 95% CI: 1.1, 2.7, AA as referent), and an inverse association with XPC 939 QQ (OR = 0.3, 95%CI: 0.2, 0.8, KK as referent). These associations were not observed among whites. For both races combined, there was interaction between the XPC 939 genotype, well-done red meat intake and colon cancer risk (OR = 1.5, 95% CI = 1.0, 2.2 for high well-done red meat and KK genotype as compared to low well-done red meat and KK genotype, p_interaction = 0.05).

Conclusions

Our data suggest that NER nsSNPs are associated with colon cancer risk and may modify the association between well-done red meat intake and colon cancer risk.

Introduction

African Americans have higher colorectal cancer incidence and mortality compared to all other racial/ethnic groups in the U.S. [1]. Differences in socioeconomic status, access to health care, environmental and dietary exposures, and genetic susceptibility may explain the disparities, though the exact contribution of each factor is unknown [2], [3]. Red meat intake has been well-studied as a risk factor for colorectal cancer [4]. High red meat intake was associated with a modest increased risk of colorectal cancer in three meta-analyses [5], [6], [7], [8].

The hypothesized etiologically relevant components in red meat include heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs), saturated fat, and nitrosamines [9], [10], [11], [12], [13]. Heme iron has also been implicated in colon carcinogenesis, though a cohort study found no association between heme iron intake and risk of colorectal cancer in Canadian women [14]. We previously reported statistically significant associations with well-done and pan-fried red meat, as well as the HCA, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), for colon cancer in the North Carolina Colon Cancer Study (NCCCS), a population-based, case-control study, of African Americans and whites [15].

HCAs and PAHs are carcinogens that can cause bulky DNA lesions. These DNA adducts can be repaired by the nucleotide excision repair pathway (NER). The NER pathway involves multiple factors in damage recognition and damage repair [16], [17], [18]. The Xeroderma Pigmentosa Group C (XPC)-RAD23B complex recognizes DNA damage, which is followed by unwinding of the DNA helix around the damaged site by the transcription factor IIH (TFIIH) complex of proteins. The TFIIH complex includes ERCC2/XPD and ERCC3/XPB [19], [20], [21]. Next, ERCC5/XPG and ERCC1/XPF make 3′ and 5′ incisions to the lesion [22], [23], [24], and the gap is filled by repair synthesis and sealed by DNA ligase [25], [26]. Decreased NER capacity in the presence of accumulating DNA damage has been associated with sporadic colorectal cancer [18].

Multiple polymorphisms within genes involved in the NER pathway have been identified [27], many of which have functional significance [17], [28], [29]. Several of these NER gene nsSNPs have been examined in relation to colorectal cancer risk, with equivocal results thus far [30]. However, few data are available for joint effects of meat intake and NER gene polymorphisms on colon cancer risk [31], [32], [33], [34], particularly among African Americans, an underserved population with higher incidence of colon cancer than other racial/ethnic groups [35]. The presence of joint effects would provide support for an underlying mechanism for our previously reported HCA-colon cancer associations that would involve the NER pathway. In the present study, we examined joint effects of meat intake and seven nsSNPS in five genes involved in NER on colon cancer risk. These nsSNPS were selected based on their putative functional impact and previous evidence of colon cancer risk associations. We hypothesize that nsSNPs in genes in the NER pathway modify associations between meat and meat-derived carcinogen (HCAs and PAHs) intake and colon cancer risk, and the extent of the effect modification varies by race.