David C. Christiani
Background: Genetic susceptibility is one of the primary hypotheses used to explain why a minority of smokers develop lung cancer. Polymorphisms of genes involved in metabolism of carcinogens have been studied as possible attenuators of risks for lung cancer. The family of glutathione S-transferase (GST) enzymes are important components of carcinogen metabolism so polymorphic differences in these enzymes may be responsible for at least part of the differences in risk. GST pi is the most expressed metabolic enzyme in the lung and it is encoded by a polymorphic gene GSTP1. These polymorphisms are a consequence of a single base-pair substitution which leads to a single amino acid change in the enzyme. This substitution results in lower enzymatic activity and is associated with higher DNA adduct formation in human lymphocytes. A polymorphism in another GST gene, GSTM1-null, results in the total loss of enzymatic function.
Polymorphic genes involved in cell cycle regulation, apoptosis, and tumor suppression have also been studied as possible risk factors for lung cancer. p53 is one of these genes and is one of the most commonly mutated genes in all human cancers. Several studies have shown that the polymorphic p53 gene is associated with a higher risk of lung cancer.
Individually, functional polymorphisms of these genes have been studied as risk factors for lung cancer; however, small sample sizes have prevented the investigation of possible increases in risk associated with having two or more at risk polymorphisms. Christiani and colleagues have carried out such an investigation of "double variants" in a large Caucasian population. Because these double variants may promote lung cancer at an earlier age, a subgroup of people 55 and younger was examined separately.
Advance: In the whole population, those with double variants had a higher risk of lung cancer compared with controls. The GSTP1 and GSTM1-null double variants had a relative risk only slightly higher (60%) than controls; however the GSTP1 and p53 double variant were twice as likely to develop lung cancer. In the younger group, the relative risks were 4- and 5-fold higher respectively.
Implication: Specific double variants of GSTP1, GSTM1-null, and p53 double variants are associated with higher lung cancer risks. This susceptibility is highest among younger individuals. Additional studies will help elucidate the possible mechanisms involved in the steps leading to carcinogenesis. Although the combined double variant risks generally had a greater than additive effect, larger sample sizes are needed to consider differences in gender and to clarify the association with early onset lung cancer.
Citation: Miller DP, Liu G, De Vivo I, Lynch TJ, Wain JC, Su L, Christiani DC. Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res. 2002 May 15;62(10):2819-23.