MULTIPLE CUTANEOUS BASAL-CELL CARCINOMAS - GLUTATHIONE-S-TRANSFERASE (GSTM1, GSTT1) AND CYTOCHROME-P450 (CYP2D6, CYP1A1) POLYMORPHISMS INFLUENCE TUMOR NUMBERS AND ACCRUAL

The genetic factors that mediate the pathogenesis of multiple primary cutaneous basal cell carcinomas (BCC) are largely unclear. Thus, some patients suffer many BCC (>30) and/or rapid accrual (number of tumours /year from first presentation) of further lesions. We have studied, in 827 English Caucasians, the influence of polymorphism in carcinogen-m etabolizing enzymes on susceptibility to this cancer. Accordingly, we describe, first, a cross-sectional analysis of the influence of GSTM1, GSTT1, CYP2D6 and CYP1A1 genotypes on tumour numbers, and secondly, a longitudinal analysis. In 169 of these cases, of the effect of these genes on tumour accrual. We have confirmed the expected importance of age and number of lesions at presentation, and male gender and skin ty pe as risk factors. Furthermore, the cross-sectional analysis showed C YP1A1 m(1)m(1) (P = 0.004; rate ratio 1.242) and CYP2D6 EM (P < 0.001, rate ratio 1.266) are associated with increased numbers of BCC. The l ongitudinal study showed, after adjustment for age and tumour number a t presentation, that GSTT1 null (P < 0.001, rate ratio 2.677) and CYP2 D6 EM (P < 0.001, rate ratio 2.154) were significant determinants of a ccrual while CYP1A1 Ile/Ile was associated with slower accrual than th e Ile/Val and Val/Val genotypes (P = 0.008, rate ratio 0.690). We beli eve these are the first genetic factors to be associated with tumour a ccrual. No significant interactions between genotypes were identified, though the combinations GSTM1 null/skin type 1 (P < 0.001, rate ratio 2.702), CYP2D6 EM/male gender (P = 0.049, rate ratio 1.279) and CYP2D 6 EM/blue+green eyes (P = 0.046, rate ratio 1.388) influenced tumour n umbers. Previous studies indicate the importance of effective repair o f UV-damaged DNA in the pathogenesis of multiple BCC; indeed the influ ence of GSTM1 may result from its ability to utilize 5'-hydroxymethylu racil. However, the finding that CYP2D6 and CYP1A1 influence tumour nu mbers and accrual indicates detoxification of unknown molecules is imp ortant and supports the view that factors other than UV are important in the pathogenesis of BCC.