Polymorphisms in Base Excision Repair Genes as Colorectal Cancer Risk Factors and Modifiers of the Effect of Diets High in Red Meat

Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, California 90089, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 10/2010; 19(12):3167-73. DOI: 10.1158/1055-9965.EPI-10-0606
Source: PubMed


A diet high in red meat is an established colorectal cancer (CRC) risk factor. Carcinogens generated during meat cooking have been implicated as causal agents and can induce oxidative DNA damage, which elicits repair by the base excision repair (BER) pathway.
Using a family-based study, we investigated the role of polymorphisms in 4 BER genes (APEX1 Gln51His, Asp148Glu; OGG1 Ser236Cys; PARP Val742Ala; and XRCC1 Arg194Trp, Arg280His, Arg399Gln) as potential CRC risk factors and modifiers of the association between diets high in red meat or poultry and CRC risk. We tested for gene-environment interactions using case-only analyses (n = 577) and compared statistically significant results with those obtained using case-unaffected sibling comparisons (n = 307 sibships).
Carriers of the APEX1 codon 51 Gln/His genotype had a reduced CRC risk compared with carriers of the Gln/Gln genotype (odds ratio (OR) = 0.15, 95% CI = 0.03-0.69, P = 0.015). The association between higher red meat intake (>3 servings per week) and CRC was modified by the PARP Val762Ala single-nucleotide polymorphisms (SNP; case-only interaction P = 0.026). This SNP also modified the association between higher intake of high-temperature cooked red meat (case-only interaction P = 0.0009).
We report evidence that the BER pathway PARP gene modifies the association of diets high in red meat cooked at high temperatures with risk of CRC.
Our findings suggest a contribution to colorectal carcinogenesis of free radical damage as one of the possible harmful effects of a diet high in red meat.

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Available from: Roman Corral, Mar 20, 2015
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    • "GST gene polymorphism may exert an effect on the risk of development of CRC, especially in the context of diet and nutritional habits, by modification of the exposure of intestinal mucosa to food-related carcinogenic agents [1]. Red meat is a potential source of carcinogens, and the amount and duration of exposure to them may be modified by GST enzymes [1, 2]. Not long ago, a systematic review was published of studies concerning the analysis of the interactions between diet and genetic factors in the development of CRC, which did not provide an unequivocal conclusion, suggesting that further studies should be carried out in this area [1]. "
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    • "O 6 CMG). [14] [15] [16] Alternatively, a recent study showed that alkyltrasferase-like (ATL) proteins can recognise and bind with high affinity to DNA containing O 6 CMG. Those enzymes do not directly de-alkylate the lesion but protect the DNA against possible damage by triggering the nucleotide excision repair (NER) system. "

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    • "The hOGG1, which is generally involved in DNA repair, has been studied extensively on its relationship with different types of cancer, such as breast [6]–[18], prostate [19]–[25], pancreatic [26], [27], bladder [28]–[34], gallbladder [35]–[38], gastric [39]–[49], colorectal [50]–[63], esophageal [64]–[68], lung [69]–[85], cervical cancers [86], [87], and so on [88]–[101]. Previous conclusions of numerous studies on the association between the hOGG1 Ser326Cys polymorphism and cancer risk remain conflicting and contradictory. "
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