XPD Polymorphism and Risk of Subsequent Cancer in Individuals with Nonmelanoma Skin Cancer Abenaa M. Brewster, 1 Anthony J. Alberg, 2 Paul T. Strickland, 3 Sandy C. Hoffman, 2 and Kathy Helzlsouer 2 1 Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston, Texas and Departments of 2 Epidemiology and 3 Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland Abstract Background: Individuals with nonmelanoma skin cancer (NMSC) are at increased risk of developing subsequent cancers. Genetic predisposition to reduced DNA repair capacity may be an underlying suscepti- bility factor explaining the excess risk of malignancies. To test this hypothesis, a cohort study was conducted to examine the association between XPD Lys751Gln polymorphism and risk of a second primary cancer in individuals with NMSC. Methods: A subgroup of 481 individuals with a history of NMSC who participated in the CLUE II community-based cohort was followed for the development of a second primary cancer. Blood specimens donated in 1989 were genotyped for the XPD Lys751Gln polymorphism using the 5V nuclease assay. Cox proportional regression with delayed entry was used to calculate the incidence rate ratio (IRR) and 95% confidence interval (95% CI) for risk of developing a second primary cancer according to XPD genotype. All statistical tests were two sided. Results: Eighty indi- viduals developed a second primary cancer. The most frequent occurring cancers were of the prostate (18%), lung (15%), and breast (15%). Persons with at least one Gln allele had an increased risk of a second primary cancer compared with the reference Lys/Lys genotype (adjusted IRR 2.22, 95% CI 1.30-3.76). When the reference category was limited to never smokers with the Lys/Lys genotype, the risk of developing a second primary cancer associated with having at least one Gln allele was increased >3-fold in both never smokers (IRR 3.93, 95% CI 1.36-11.36) and ever smokers (IRR 6.14, 95% CI 2.17-17.37). Conclusion: These findings suggest that individuals with NMSC who have the variant XPD Gln allele are at increased risk of devel- oping a second primary cancer. (Cancer Epidemiol Biomarkers Prev 2004;13(8):1271 – 5) Background Nonmelanoma skin cancers (NMSC) are the most common cancers diagnosed in the United States. Over 1 million new cases of basal and squamous cell carcinomas of the skin occur annually, and exposure to UV radiation is the leading risk factor (1, 2). UV radiation causes skin carcinogenesis by inducing cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts that form between adjacent pyrimidine bases (3). Suboptimal repair of these DNA lesions by the nucleo- tide excision repair (NER) pathway leads to the accumulation of mutations in important cell cycle regulatory genes that may eventually result in tumor development (4, 5). The overall prognosis of NMSC is excellent, but several studies have shown that affected individuals are at increased risk of developing subsequent cutaneous and noncutaneous malignancies (6-19) and have a higher overall cancer mortality rate (20, 21) compared with the general population. The excess incidence of noncuta- neous malignancies in individuals with a prior NMSC is unexplained. One hypothesis is that genetic predisposi- tion to reduced DNA repair capacity may be an underlying susceptibility factor, increasing the risk of a subsequent malignancy (19, 22). Polymorphisms of genes involved in the major NER pathway are of particular interest as candidate genes that may contribute to interindividual variations in DNA repair capacity and cancer susceptibility. In addition to the removal of mutagenic UV-induced photoproducts, the NER pathway is responsible for the removal of bulky and helical distorting DNA adducts induced by chemical carcinogens and cellular metabolites (3, 23). Given the involvement of the NER pathway in the removal and repair of a wide variety of carcinogenic DNA lesions, defects in this pathway may predispose an individual to both cutaneous and noncutaneous malig- nancies. Within this pathway, a plausible candidate sus- ceptibility gene is the common XPD polymorphism in exon 23 that causes an amino acid substitution of lysine for glutamine (24). The normal functioning XPD protein Received 12/29/03; revised 3/3/04; accepted 3/11/04. Grant support: National Institute of Aging grant 5U01AG018033, National Cancer Institute grant 5U01CA086308, and National Institute of Environmental Health Sciences grant P30 ES03819. Minority Supplement of Clinical Oncology Research Career Development Program (K12-CA01709) from the National Cancer Institute (A.M. Brewster) and KO7 award (CA73790) from the National Cancer Institute (A.J. Alberg). 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: Kathy Helzlsouer, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Suite E6132, 615 North Wolfe Street, Baltimore, MD 21205. Phone: 410-955-9727; Fax: 410-614-2632. E-mail: khelzlso@jhsph.edu Copyright D 2004 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 1271 Cancer Epidemiol Biomarkers Prev 2004;13(8). August 2004 on July 24, 2021. © 2004 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from