Glutathione S-transferase GSTP1 and cyclin D1 genotypes: association with numbers of basal cell carcinomas in a patient subgroup at high-risk of multiple tumours

We previously described associations between basal cell carcinoma (BCC) num bers and allelic variants at loci that mediate host response to ultraviolet radiation (UV). These associations were largely exerted in cases with the multiple presentation phenotype (MPP). This phenotype describes patients wh o present at their first or a later presentation with a cluster of BCC (2-1 0 new BCC). Remaining BCC cases have the single presentation phenotype (SPP ) and mag develop more than one BCC but only have single new lesions at any presentation. We proposed that the MPP cases comprise a high-risk group as they suffer significantly more lesions than SPP cases. We are attempting t o determine, in the total BCC case group and subgroups, how many genes infl uence BCC numbers and their relative importance. In this study, we assessed the influence of two further candidates, glutathione S-transferase GSTP1 a nd cyclin D1 (CCND1), on tumour numbers in a total group of 457 patients co mprising MPP and SPP cases. The relative importance of these genes in compa rison with occupational UV exposure and host response (skin type) was also considered. We found that the frequencies of GSTP1 genotypes based on the I le(105) and Val(105)-expressing alleles and CCND1 AA, AG, GG genotypes were similar in MPP and SPP cases and that there were no significant associatio ns between GSTP1 or CCND1 genotypes and BCC numbers in the total or SPP gro ups. However, in the MPP cases, GSTP1 Val(105)/Val(105) was associated with more tumours (P = 0.05, reference GSTP1 Ile(105)/Ile(105)). Inclusion of s kin type and indoor/outdoor occupation in the negative binomial regression models did not alter the associations of these genotypes with tumour number s. DNA from 258 cases was analysed to identify GSTP1*A (Ile(105)-Ala(114)), GSTP1*B (Val(105)-Ala(114)), GSTP1*C (Val(105)-Val(114)) and GSTP1*D (Ile( 105)-Val(105)). In SPP cases, there was no association between BCC numbers and GSTP1 BB, though the association with GSTP1 BC approached significance (P = 0.09). In MPP cases, GSTP1 BC was associated with BCC numbers (P = 0.0 3). We also found that the interaction term, GSTP1 Val(105)/Val(105) with C CND1 AA, was associated with BCC numbers in the total (P = 0.001) and MPP ( P = 0.006) but not SPP (P = 0.68) groups. In a stepwise model including GST P1 Val(105)/Val(105), CCND1 AA and their interaction terms as well as GSTM1 , GSTT1 and CYP2D6 genotypes, skin type 1 and gender, the combination of ge notypes was the best predictor of BCC numbers. These data suggest that stud y of further genes involved in cell-cycle control and protection from oxida tive stress will be useful, particularly in high-risk subgroups. Pharmacoge netics 10:545-556 (C) 2000 Lippincott Williams & Wilkins.