Copy number variations of GSTT1 and GSTM1, colorectal cancer risk and possible effect modification of cigarette smoking and menopausal hormone therapy

Abstract

Copy number variations (CNVs) of the glutathione-S-transferase y-1 (GSTT1) and glutathione-S-transferase l-1 (GSTM1) gene loci can lead to complete lack of enzyme and have been associated with colorectal cancer (CRC) risk. As GSTs are involved in the detoxification of xenobiotics, CNVs may modify CRC risk associated with smoking exposure and menopausal hormone therapy (MHT) use. We investigated CRC risk associated with GSTT1 and GSTM1 CNVs and their interaction with smoking in 1,796 cases and 1,806 age-, sex-and residence-matched controls from a German population-based case-control study (DACHS). The interaction with MHT was assessed in the subset of 684 postmenopausal female cases and 681 controls. Trimodular genotypes (0/0, 1/0 and 1/1) were determined with relative quantification based on multiplex real-time polymerase chain reaction. The associations with CRC risk as well as possible effect modifications were evaluated using conditional logistic regression analysis. CNVs of GSTT1 and GSTM1 were not significantly associated with CRC risk. Compared to the 1/1 genotype, odds ratios (ORs) for the 0/1 genotype and the 0/0 genotype were 0.89 [95% confidence interval (CI): 0.77-1.04] and 0.97 (95% CI: 0.80-1.18) for GSTT1, and 0.99 (95% CI: 0.78-1.27) and 1.03 (95% CI: 0.81-1.31) for GSTM1. Compared to the nonnull genotype, ORs for the null-genotype were 1.04 (95% CI: 0.87-1.23) for GSTT1 and 1.03 (95% CI: 0.91-1.18) for GSTM1. No significant interaction with smoking and MHT use was observed. Our study does not provide evidence for a strong association between CRC risk and CNVs of GSTT1 or GSTM1 or for an effect modification of smoking or MHT use.Glutathione transferases (GSTs) are a family of enzymes that catalyze the conjugation of glutathione with charged compounds, which leads to detoxification and neutralization of various exogenous and endogenous substances.1 Copy number variations (CNVs), which can lead to decreased enzyme activity and also result in gene deletion and consequently complete lack of enzyme, exist in the glutathione S-transferase l-1 (GSTM1) and glutathione S-transferase y-1 (GSTT1) gene loci. 2,3 . Polymorphisms in the respective genes have been linked to altered cancer susceptibility and drug resistance. 4 In comparison to having at least one gene copy, meta-analyses found for Caucasians an increased risk by 15% and 32% for colorectal cancer (CRC) associated with the null genotype of GSTM1 and GSTT1, respectively. 5-7 However, when differentiated by study design, no association was observed for GSTT1 in population-based studies.6 The majority of the published studies on GSTM1 and GSTT1 polymorphisms and CRC risk used genotyping methods, which were incapable of distinguishing between individuals with one or two copies of the respective genes.8 As trimodular genotype-phenotype correlations for GSTM1 and GSTT1 genes have been observed, 2,3 this is a potential source for inconsistencies. 8 The genetic variation of the GSTs might affect genetic susceptibility for CRC, for example, by modifying the...

Copy Number Variation of GSTT1 and GSTM1 and the Risk of Prostate Cancer in a Caribbean Population of African Descent

“…Evidence for duplication of GSTM1 or GSTT1 has been reported in Caucasian populations but at a substantially lower prevalence than in our study population. Among 10271 Danish subjects, only 24 individuals (0.2%) carried more than two copies of GSTM1 or GSTT1 [23]; in two studies of German subjects including 1320 [24] and 3602 [25] individuals, the frequency of GSTM1 duplication was between 0.08% and 0%, and the frequency of GSTT1 duplication 0% and 0.14%, respectively.…”

The Interaction of Smoking with Gene Polymorphisms on Four Digestive Cancers: A Systematic Review and Meta-Analysis

“…Forty-three studies were performed in Asia, 11 studies were performed in Europe, 10 studies were performed in the Americas, and 3 studies were performed in Africa. Among all identified articles, 30 evaluated GSTM1 polymorphism 19 - 48 , 18 evaluated GSTT1 polymorphism 20 - 24 , 30 - 32 , 34 , 35 , 40 , 42 - 48 , 12 evaluated GSTP1 polymorphism 11 , 22 , 30 , 32 , 34 , 35 , 42 , 49 - 53 , 8 evaluated CYP1A1 IIe462Val polymorphism 9 , 27 , 28 , 54 - 58 , 7 evaluated CYP1A1 MspI polymorphism 26 , 28 , 45 , 54 , 57 , 58 , 8 evaluated NAT2 polymorphism 24 , 28 , 36 , 38 , 46 , 59 - 61 , 6 evaluated SULT1A1 polymorphism 24 , 45 , 62 - 65 , 8 evaluated hOGG1 polymorphism 66 - 73 , 7 evaluated XRCC1 polymorphism 52 , 67 , 69 , 74 - 77 , and 6 evaluated p53 polymorphism 78 - 83 .…”

Genome‐wide expression profiling‐based copy number variations and colorectal cancer risk in Chinese

“…There are also limitations. First, although several CNVs presented correlations with gene expressions in the whole genome, since the associations between CNVs located on GSTT1 , UGT2B17 , and GSTM1 and colorectal cancer risks have been explored elsewhere previously, the current study only focused on the CNV in HLA‐DQA1 and HLA‐DQB1 . Second, the population for the association study between CNVs and susceptibility of colorectal cancer is not large enough.…”