|
|||||
|
|
Multiple cutaneous basal cell carcinomas: glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) polymorphisms influence tumour numbers and accrual |
|
| Authors: | Lear, John T. Heagerty, Adrian H.M. Smith, Andrew Bowers, Bill Payne, Christopher Rowland Smith, C.A.Dale Jones, Peter W. Gilford, Janice Yengi, Lilian Alldersea, Julie Fryer, Anthony A. Strange, Richard C. |
| Affiliation: | 1Department of Dermatology, North Staffordshire Hospital, Hartshill Stoke-on-Trent, Staffordshire 2Department of Dermatology, Royal Cornwall Hospitals 3Department of Dermatology, William Harvey Hospital Kent 4Department of Pathology, University of Edinburgh Medical School Edinburgh 5Department of Mathematics, Keele University Staffordshire 6Centre for Pathology and Molecular Medicine, School of Postgraduate Medicine, Keele University, North Staffordshire Hospital Stoke-on-Trent, Staffordshire, UK |
| Abstract: | The genetic factors that mediate the pathogenesis of multipleprimary 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 furtherlesions. We have studied, in 827 English Caucasians, the influenceof polymorphism in carcinogen-metabolizing enzymes on susceptibilityto this cancer. Accordingly, we describe, first, a cross-sectionalanalysis of the influence of GSTM1, GSTT1, CYP2D6 and CYP1A1genotypes on tumour numbers, and secondly, a longitudinal analysis,in 169 of these cases, of the effect of these genes on tumouraccrual. We have confirmed the expected importance of age andnumber of lesions at presentation, and male gender and skintype as risk factors. Furthermore, the cross-sectional analysisshowed CYP1A1 m1m1 (P = 0.004; rate ratio 1.242) and CYP2D6EM (P < 0.001, rate ratio 1.266) are associated with increasednumbers of BCC. The longitudinal study showed, after adjustmentfor age and tumour number at presentation, that GSTT1 null (P<0.001, rate ratio 2.677) and CYP2D6 EM (P< 0.001, rate ratio2.154) were significant determinants of accrual while CYP1A1Ile/Ile was associated with slower accrual than the Ile/Valand Val/Val genotypes (P = 0.008, rate ratio 0.690). We believethese are the first genetic factors to be associated with tumouraccrual. No significant interactions between genotypes wereidentified, 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 CYP2D6 EM/blue+green eyes (P = 0.046,rate ratio 1388) influenced tumour numbers. Previous studiesindicate the importance of effective repair of UV-damaged DNAin the pathogenesis of multiple BCC; indeed the influence ofGSTM1 may result from its ability to utilize 5'-hydroxymethyluracil.However, the finding that CYP2D6 and CYP1A1 influence tumournumbers and accrual indicates detoxification of unknown moleculesis important and supports the view that factors other than UVare important in the pathogenesis of BCC. |
| Keywords: | |
| 本文献已被 Oxford 等数据库收录！ | |