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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    ABSTRACT: Increasingly often, molecular studies of colorectal cancer focus on low penetrance genes. Among the factors potentially modifying the risk of contracting colorectal cancer is the glutathione S-transferase (GST) gene family, encoding enzymes of the glutathione transferase type. Proteins of the GST family (glutathione S-transferases) are enzymes detoxifying a wide range of hazardous substances, such as reactive oxygen species (ROS) or xenobionts. Thus, their role, among other things, is the protection of DNA against oxidative damage, which may lead to mutations, and in consequence, favour carcinogenesis. GST gene polymorphisms may affect the functioning of the encoded enzymes, exerting an effect on the level of DNA damage, and therefore may have an indirect influence on the risk of the development of cancer. At present, there are many studies available concerning GST gene polymorphisms as factors modulating the risk of developing cancer, including colorectal cancer.
    Contemporary Oncology / Wspólczesna Onkologia 05/2014; 18(4):219-21. DOI:10.5114/wo.2014.41388 · 0.22 Impact Factor
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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. "
    Rapid Communications in Mass Spectrometry 01/2013; · 2.25 Impact Factor
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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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    ABSTRACT: Human oxoguanine glycosylase 1 (hOGG1) in base excision repair (BER) pathway plays a vital role in DNA repair. Numerous epidemiological studies have evaluated the association between hOGG1 Ser326Cys polymorphism and the risk of cancer. However, the results of these studies on the association remain conflicting. To derive a more precise estimation of the association, we conducted a meta-analysis. A comprehensive search was conducted to identify the eligible studies of hOGG1 Ser326Cys polymorphism and cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. We found that the hOGG1 Ser326Cys polymorphism was significantly associated with overall cancer risk (Cys/Cys vs. Ser/Ser: OR = 1.19, 95%CI = 1.09-1.30, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.16, 95%CI = 1.08-1.26, P<0.001). Moreover, in subgroup analyses by cancer types, the stronger significant association between hOGG1 Ser326Cys polymorphism and lung cancer risk was found (Cys/Cys vs. Ser/Ser: OR = 1.29, 95%CI = 1.16-1.44, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.22, 95%CI = 1.12-1.33, P<0.001). The significant effects of hOGG1 Ser326Cys polymorphism on colorectal, breast, bladder, prostate, esophageal, and gastric cancer were not detected. In addition, in subgroup analyses by ethnicities, we found that the hOGG1 Ser326Cys polymorphism was associated with overall cancer risk in Asians (Cys/Cys vs. Ser/Ser: OR = 1.21, 95%CI = 1.10-1.33, P<0.001). This meta-analysis showed that hOGG1 326Cys allele might be a low-penetrant risk factor for lung cancer.
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