A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer

Abstract

Susceptibility to colorectal cancer, one of the most common forms of cancer in the Western world, has been associated with several environmental and dietary risk factors. Dietary exposure to food derived heterocyclic amine carcinogens and polycyclic aromatic hydrocarbons have been proposed as specific risk factors. Many polymorphic Phase I and Phase II drug metabolizing enzymes are responsible for the metabolism and disposition of these compounds and it is therefore possible that inheritance of specific allelic variants of these enzymes may influence colorectal cancer susceptibility. In a multicenter case-control study, 490 colorectal cancer patients and 593 controls (433 matched case-control pairs) were genotyped for common polymorphisms in the cytochrome P450 (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C9, CYP2C19 and CYP2D6), glutathione S-transferase (GSTM1, GSTP1 and GSTT1), sulfotransferase (SULT1A1 and SULT1A2), N-acetyl transferase 2 (NAT2), NAD(P)H:quinone oxidoreductase (NQO1), methylenetetrahydrofolate reductase (MTHFR), and microsomal epoxide hydrolase (EPHX1) genes. Matched case-control analysis identified alleles associated with higher colorectal cancer risk as carriage of CYP1A1*2C (OR = 2.15, 95% CI 1.36-3.39) and homozygosity for GSTM1*2/*2 (OR = 1.53, 95% CI 1.16-2.02). In contrast, inheritance of the CYP2A6*2 (OR = 0.51, 95% CI 0.28-1.06), CYP2C19*2 (OR = 0.72, 95% CI 0.52-0.98) and the EPHX1(His113) alleles were associated with reduced cancer risk. We found no association with colorectal cancer risk with NAT2 genotype or any of the other polymorphic genes associated with the metabolism and disposition of heterocyclic amine carcinogens. This data suggests that heterocyclic amines do not play an important role in the aetiology of colorectal cancer but that exposure to other carcinogens such as polycyclic aromatic hydrocarbons may be important determinants of cancer risk.

GSTM1 gene polymorphism and the risk of colorectal cancer in a Saudi Arabian population

“…Furthermore, GSTM1 null genotype carriers are at a greater risk of developing colorectal malignancies. The results of this study are in agreement with those of numerous studies that have reported a significant effect of the GSTM1 null genotype on susceptibility to colorectal cancer (Sachse et al, 2002;Huang et al, 2006;Csejtei et al, 2008;Hlavata et al, 2010;Cai et al, 2014;Teng et al, 2014). The incidence of the null genotype in the current study was higher than that in similar studies that reported significant results (Table 3).…”

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

“…The results were similar to that from our analysis of dietary methyl status (P test for interaction >0.13; data not shown). Because this analysis of interaction with dietary methyl status was based on grouping the variant carriers, and the main effect of MTHFR Ala 222 Val has been observed to behave in a recessive manner, we also conducted this analysis with Vitamin B 12 is transported by TCN II and is a cofactor to MTR, the function of which is related to MTRR and BHMT, thus, we examined whether total vitamin B 12 intake (including dietary and supplemental sources) modified the associations for BHMT Arg 239 (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) and nested case-control studies (10,(46)(47)(48). In addition, our finding that the inverse association was stronger for colon cancers versus rectal cancers was consistent with some (47,48), although not all previous studies (38,40,46).…”

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

“…Frequencies of both the 677T and 1298C alleles are generally in the range of 30-35% in Caucasians. [11][12][13][14][15][16][17][18][19] The relatively lower frequency of the 1298C allele makes it somewhat difficult to study the relation of MTFHR A1298C to colorectal cancer in Japanese.…”

“…13,14) However, other case-control studies have failed to substantiate a protective association with the 677TT genotype in various countries, including the United States. [15][16][17][18][19][20][21] Few studies have addressed the association between the MTHFR A1298C polymorphism and colorectal cancer. [14][15][16]22) Of these, only one study showed a decreased risk of colorectal cancer associated with the 1298CC genotype.…”