Genetic Variation in XPD, Sun Exposure, and Risk of Skin Cancer Jiali Han, 1,5 Graham A. Colditz, 1,2,4 Jun S. Liu, 3,6 and David J. Hunter 1,2,5 1 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School; 2 Department of Epidemiology, 3 Department of Biostatistics, 4 Harvard Center for Cancer Prevention, and 5 Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts and 6 Department of Statistics, Harvard University, Cambridge, Massachusetts Abstract The XPD gene is involved in the nucleotide excision repair pathway removing DNA photoproducts induced by UV radiation. Genetic variation in XPD may exert a subtle effect on DNA repair capacity. We assessed the associations between two common nonsynonymous poly- morphisms (Asp 312 Asn and Lys 751 Gln) with skin cancer risk in a nested case-control study within the Nurses’ Health Study (219 melanoma, 286 squamous cell carci- noma, 300 basal cell carcinoma, and 874 controls) along with exploratory analysis on the haplotype structure of the XPD gene. There were inverse associations between the Lys 751 Gln and Asp 312 Asn polymorphisms and the risks of melanoma and squamous cell carcinoma. No association was observed between these two polymorphisms and basal cell carcinoma risk. We also observed that the association of the 751 Gln allele with melanoma risk was modified by lifetime severe sunburns, cumulative sun exposure with a bathing suit, and constitutional suscepti- bility score (P for interaction = 0.03, 0.04, and 0.02 respectively). Similar interactions were also observed for the Asp 312 Asn. Our data suggest these two XPD non- synonymous polymorphisms may be associated with skin cancer risk, especially for melanoma. (Cancer Epidemiol Biomarkers Prev 2005;14(6):1539 – 44) Introduction Skin cancer is the most common neoplasm in Caucasians in the United States. The genotoxic effect of sunlight exposure has been clearly shown in the etiology of both melanoma and nonmelanocytic skin cancer (1-3). One important defense mechanism against skin cancer is the ability to repair DNA damage induced by UV light. It has been suggested that reduced DNA repair capacity (DRC) is a susceptibility factor predisposing individuals to skin cancer (4-7). The predomi- nant form of UV-induced DNA damage is DNA photo- products caused by the direct absorption of UVB by DNA. Cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimi- done photoproducts constitute the two major DNA photo- products (2). DNA photoproducts are mainly removed by the nucleotide excision repair (NER). The NER is a versatile repair system to remove a variety of bulky, helix-distorting lesions, including UV photoproducts and bulky adducts (8, 9). Individuals with xeroderma pigmentosum, deficient in the NER, have a >1,000-fold increased risk of skin cancer. Human XPD maps to chromosome 19q13.3 and spans f54 kb. It comprises 23 exons and is 761 amino acids in length. The XPD gene encodes an ATP-dependent DNA helicase involved in the NER and in basal transcription as part of the transcription factor TFIIH. Disruption of the mouse Xpd gene results in preimplantation lethality (10). Mutations in the XPD gene lead to NER defects (11) and three clinical syndromes, Cockayne syndrome, xeroderma pigmentosum, and tricho- thiodystrophy, depending on the location of the mutation (9, 12). In addition, the XPD and p53 proteins can interact with each other to modulate apoptosis and the NER. The p53 binds and modulates the helicase activity of the TFIIH, and the repair of UV-induced dimers was attenuated in Li-Fraumeni syn- drome cells (heterozygote p53 mutant; ref. 13). A deficiency in p53-mediated apoptosis was reported in XPD lymphoblastoid cell lines and fibroblasts from xeroderma pigmentosum patients with germ line mutations in the XPD gene (14, 15). We evaluated two common nonsynonymous XPD poly- morphisms (Asp 312 Asn and Lys 751 Gln) in relation to skin cancer risk in a nested case-control study within the Nurses’ Health Study along with exploratory analysis on the haplotype structure of the XPD gene. We further investigated the hypothesis that XPD genetic variants modify the associations of sunlight-related risk factors with skin cancer risk. Materials and Methods Study Population. The Nurses’ Health Study was estab- lished in 1976, when 121,700 female registered nurses between ages 30 and 55 years completed a self-administered question- naire on their medical histories and baseline health-related exposures. Updated information has been obtained by ques- tionnaires every 2 years. Between 1989 and 1990, blood samples were collected from 32,826 of the cohort members. Eligible cases in this study consisted of women with incident skin cancer from the subcohort who gave a blood specimen, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases with a diagnosis anytime after blood collection up to June 1, 1998 and melanoma cases (including in situ cases) up to June 1, 2000 with no previously diagnosed skin cancer. All available pathologically confirmed melanoma and SCC cases and 300 self-reported BCC cases randomly selected from f2,600 available self-reported BCC cases were included. The validity of self-report of BCC is high in this medically sophisticated population (90%; ref. 16). All the SCC and BCC cases had no history of melanoma diagnosis. A common control series (case/control, 1:1) was randomly selected from participants who gave a blood sample and were free of diagnosed skin cancer up to and including the Cancer Epidemiology, Biomarkers & Prevention 1539 Cancer Epidemiol Biomarkers Prev 2005;14(6). June 2005 Received 11/16/04; revised 3/22/05; accepted 4/7/05. Grant support: NIH grants CA97746 and CA87969 and Harvard Specialized Programs of Research Excellence in Skin Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Jiali Han, Channing Laboratory, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115. Phone: 617-525-2098; Fax: 617-525-2008. 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