Five Glutathione S-Transferase Gene Variants in 23,452 Cases of Lung Cancer and 30,397 Controls: Meta-Analysis of 130 Studies

Zheng Ye, Honglin Song, Julian P T Higgins, Paul Pharoah and John Danesh

PLOS Medicine, 2006, vol. 3, issue 4, 1-

Abstract: Background: Glutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results. Methods and Findings: Literature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms ( GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14–1.23) and 1.09 (95% CI: 1.02–1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95–1.14) and 0.99 (95% CI: 0.86–1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99–1.09), 1.15 (95% CI: 0.95–1.39), and 1.05 (95% CI: 0.89–1.23), respectively. Conclusions: The risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies. Large meta-analysis finds little evidence for a link between gene variants encoding inactive or less active variants of detoxifying enzymes and lung cancer risk. Background: Genes and the environment determine a person's risk of cancer. For some cancers, strong environmental risk factors have been identified. One such example is lung cancer, where the large majority of cases are caused by smoking. However, some people who never smoke get lung cancer, and some heavy smokers do not. To help understand such cases, scientists have studied a group of genes called glutathione S-transferase genes. These genes contain the genetic information to make a group of proteins, the glutathione s-transferases, which detoxify environmental poisons such as those contained in cigarette smoke. Different people have slightly different versions of these genes. Some of these gene variants are thought to result in less active or even completely inactive proteins. Scientists have wondered whether these different gene variants influence the lung cancer risk in smokers and non-smokers. To find out, they have done a lot of studies, some small, some large, to test whether there are associations between particular glutathione s-transferase gene variants and the risk of lung cancer. Why Was This Study Done?: Such association studies compare a group of people with lung cancer and a very similar group without lung cancer. Researchers determine the genetic make-up of both groups and ask whether a particular gene variant is more common among either the cancer patients (the “cases”) or the people without cancer (the “controls”). A variant that is more common among the cases might convey a risk, and one that is more common among the controls might convey some level of protection. The larger the studies are, and the more similar the cases and controls are, the better the chance to detect a “real” association. However, association studies are notoriously difficult to interpret, and most scientists agree that several independent studies are necessary before one can be reasonably sure that a particular gene variant conveys a risk or a protection. A rigorous way to summarize and integrate the results from several individual association studies is to do what is called a meta-analysis. What Did the Researchers Do and What Did They Find?: These researchers did such a meta-analysis of 130 studies. Together, the studies tested possible associations between five relatively common variants in four glutathione s-transferase genes and the occurrence of lung cancer. All of the variants tested resulted in either less active or inactive versions of the proteins. Some of the individual studies had found associations between one or several of the variants and lung cancer (suggesting that they conveyed a risk), others had not. Altogether, the studies included data from over 23,000 lung cancer patients and 30,000 control individuals without lung cancer. After summarizing all of the results, it became clear that none of the five variants, not even the ones that resulted in inactive proteins, conveyed a clearly strong risk for lung cancer. What Does This Mean?: A rigorous assessment of the results to date suggests that none of the five variants conveys a clearly strong risk for lung cancer in the general population. The gene variants included were some of the obvious ones to study, but there might be others that have a strong influence on an individual's risk to get lung cancer. It is also possible that some of these gene variants convey a stronger risk in some subgroups, for example, in particular ethnic groups that share a common genetic background. Additional studies that look specifically at the risk in particular subgroups would be needed to find out whether this is indeed the case. And much larger studies would be needed to determine reliably whether there are genes that convey a small or moderate risk for (or protection against) lung cancer. Where Can I Find More Information Online?: The following pages provide information on lung cancer and cancer genetics.

Date: 2006
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DOI: 10.1371/journal.pmed.0030091

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