POLYMORPHISM AT THE GLUTATHIONE-S-TRANSFERASE LOCUS GSTM3 - INTERACTIONS WITH CYTOCHROME-P450 AND GLUTATHIONE-S-TRANSFERASE GENOTYPES AS RISK-FACTORS FOR MULTIPLE CUTANEOUS BASAL-CELL CARCINOMA

The influence of polymorphism in the glutathione S-transferase, GSTM3 gene on susceptibility to cutaneous basal cell carcinoma (BCC) has bee n investigated. We have reported previously two GSTM3 alleles, GSTM3A and GSTM3B, distinguished by a recognition motif for the YY1 transcr iption factor in GSTM3()B. In this study, immunohistochemistry was us ed to identify GSTM3 expression in the epidermis of skin samples from 11 controls and 9 patients with BCC. A PCR method was used to identify GSTM3A and GSTM3*B and thereby the GSTM3 AA, GSTM3 AB, and GSTM3 BE genotypes in 300 controls and 286 Caucasians with 1-35 primary BCCs. G enotypes at GSTM1, GSTT1, and the cytochrome P450 CYP1A1 and CYP2D6 lo ci were also determined. Frequencies of GSTM3, GSTM1, GSTT1, CYP2D6, a nd CYP1A1 genotypes in the cases and controls were not different. Divi ding the BCC cases into groups of 92 patients with 1 lesion and 194 pa tients with 2-35 lesions showed that the frequencies of GSTM3 BE (2.6% ) and GSTM1 A/B (1.3%) in the group with 2-35 tumors were almost signi ficantly lower than in the group with 1 lesion (7.6%, exact P = 0.0601 , chi(1)(2) = 3.390; 6.5%, exact P = 0.055, chi(1)(2) = 4.946, respect ively). Within the cases with 2-35 tumors, a Poisson regression model was used to identify genotypes, characteristics such as skin type, and interactions between genotypes and characteristics associated with in creasing numbers of tumors. This showed, after correction for male gen der and age, that GSTM3 AA was not associated with risk of increased n umbers of tumors, although in combination with skin type 1, GSTM1 null , and CYP1A1 m1m1, the genotype did confer increased risk (P < 0.001, rate ratio, 2.058; P < 0.001, rate ratio, 1.606; P < 0.001, rate ratio , 1.470, respectively). The data suggest that, Like other allelic GST, GSTM3 influences cancer risk. As GSTM3 AA was associated with increas ed tumor numbers, it appears that YY1 acts as an activator of the reco gnition moth in GSTM3B.