Characterization of the Human Class Mu Glutathione S-Transferase Gene Cluster and the GSTM1Deletion

Abstract

A partial physical map has been constructed of the human class Mu glutathione S-transferase genes on chromosome 1p13.3. The glutathione S-transferase genes in this cluster are spaced about 20 kilobase pairs (kb) apart, and arranged as 5 -GSTM4-GSTM2-GSTM1-GSTM5-3 . This map has been used to localize the end points of the polymorphic GSTM1 deletion. The left repeated region is 5 kb downstream from the 3 -end of the GSTM2 gene and 5 kb upstream from the beginning of the GSTM1 gene; the right repeated region is 5 kb downstream from the 3 -end of the GSTM1 and 10 kb upstream from the 5 -end of the GSTM5 gene. The GSTM1-0 deletion produces a novel 7.4-kb HindIII fragment with the loss of 10.3-and 11.4-kb HindIII fragments. The same novel fragment was seen in 13 unrelated individuals (20 null alleles), suggesting that most GSTM1-0 deletions involve recombinations between the same two regions. We have cloned and sequenced the deletion junction that is produced at the GSTM1-null locus; the 5 -and 3 -flanking regions are more than 99% identical to each other and to the deletion junction sequence over 2.3 kb. Because of the high sequence identity between the left repeat, right repeat, and deletion junction regions, the crossing over cannot be localized within the 2.3-kb region. The 2.3-kb repeated region contains a reverse class IV Alu repetitive element near one end of the repeat.The glutathione S-transferases (EC 2.5.1.18) are a superfamily of catalytic and binding proteins that detoxify chemical carcinogens (1). Based primarily on protein sequence similarity, the soluble glutathione S-transferases have been divided into four protein families: classes Alpha, Mu, Pi, and Theta. Class Alpha and Mu families typically contain four or more members in mammalian genomes. In humans, a large fraction of the population carries polymorphic deletions for the class Mu GSTM1 gene (about 50% of the population is homozygous GSTM1-null; Ref. 2) and the class Theta GSTT1 gene (40% of the population is homozygous GSTT1-null; Ref. 3).Significant associations between the GSTM1-0 deletion and increased cancer incidence in case/control studies have been reported for lung (4 -6), bladder (7,8), and skin cancer (9 -11). Both positive and negative results have been reported for associations between GSTM1-0 and cancer risk. A large study (6) on the effect of the GSTM1 deletion and lung cancer among caucasians and African Americans in southern California suggests that, in these populations at least, the association of the GSTM1-0 deletion and cancer is not strong. London et al. (6) found a significant association between lung cancer and the GSTM1 deletion only in cancer patients with a history of smoking but who had smoked less than 40 pack-years (e.g. 2 packs/ day for 20 years) (odds ratio ϭ 1.77, 95% CI 1 ϭ 1.11-2.82). After regression to remove age, sex, and smoking history effects, no significant association was found for total lung cancer cases or for cases where the patient had smoked more than 40 pack-years. These authors reviewed the lit...

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