Genetic variation, DNA repair and skin cancer

The genotoxic effect of sunlight exposure has been demonstrated in the etiology of both melanoma and non-melanocytic skin cancer. W radiation is capable of causing a wide range of lesions in DNA. One important defense mechanism against skin cancer is the ability to repair UV-induced DNA damage. We assessed the association of polymorphisms in candidate DNA repair genes in three important DNA repair pathways (XRCC1 in base excision repair; XPD in nucleotide excision repair; XRCC2, XRCC3, and LigaseIV in double strand break repair) with the risks for melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in a nested case-control study within the Nurses' Health Study (805 incident cases including 219 melanoma, 286 SCC, and 300 BCC, and 873 controls). We inferred the haplotype structures for these 5 genes. We further examined whether the candidate polymorphisms may modify the associations between the sunlight-related exposures and the risk of skin cancer.; We observed that XRCC1 194Trp carriers were at borderline significantly increased risk of SCC, and the XRCC1 399G1n allele was significantly associated with decreased risk of SCC. We also observed significant interactions between the XRCC1 399Gln allele and family history of skin cancer and history of severe lifetime sunburns on SCC risk. There were non-significant inverse relationships between the XPD Lys751Gln and Asp312Asn polymorphisms and the risks of melanoma and SCC. We also observed that the association of the XPD 751Gln allele with melanoma risk was significantly modified by a constitutional susceptibility score, lifetime severe sunburns, and cumulative sun exposure while wearing a bathing suit. We observed that the variant allele of XRCC3 Thr241Met was significantly inversely associated with the risks of SCC and BCC. The variant alleles of XRCC2 G30833A and XRCC3 A4552C were significantly associated with an increased risk of BCC. We also observed a significant interaction between the XRCC3 Thr241Met and cumulative sun exposure while wearing a bathing suit on SCC risk, and a significant interaction between the XRCC3 Thr241 Met and lifetime sunburns on melanoma risk. These data suggest that the genetic polymorphisms in DNA repair genes may confer inherited predisposition to skin cancer.