The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy developing in young men, has increased several-fold since the 1950s. Despite three decades of research in human populations, the etiology of TGCC remains obscure and our knowledge of risk factors is limited largely to demographic characteristics and a history of undescended testes. Clinical, non-human experimental, and epidemiologic studies of TGCC have provided evidence that exposure to abnormal levels of steroid hormones, either in utero, perinatally, and/or early in life, may be a key etiologic factor for TGCC. Epidemiologic support of this hypothesis, however, has been inconsistent, a phenomena attributable at least in part to the limited ability of interview and medical record data to capture the relevant exposures. Recent progress in identifying polymorphisms in genes contributing to endogenous steroid hormone metabolism presents an opportunity to expand beyond the scope of prior epidemiologic studies by addressing the hypothesized hormonal etiology of TGCC at the molecular genetic level. Specifically, we propose to test the hypothesis that inherited variation in genes involved in stimulating testicular steroidogenesis, synthesizing and metabolizing testosterone, and androgen signaling, is related to the risk of developing TGCC. A population-based case-control study will be conducted. Cases will be approximately 280 incident cases of TGCC diagnosed between October 1998 and September 2003 and who are residents of a three county metropolitan region in western Washington State. Demographically similar controls (n=840) will be ascertained from the general population using random digit telephone dialing. Cases and controls will be interviewed in-person regarding medical and lifestyle histories. A venous blood sample will be obtained from all consenting participants and peripheral leukocytes isolated and stored. Genomic DNA extracted from leukocytes will be tested for variants in the following genes involved in 1) the stimulation of testicular steroidogenesis (Luteinizing Hormone and Insulin-Like Growth Factor-1), 2) the synthesis and metabolism of testosterone (Cytochrome p450 11a [CYP11a], CYP17, 3Beta-Hydroxysteroid Dehydrogenase Type II, CYP3A4, and UDP-Glucuronosyltransferase 2B15), and 3) testosterone signaling (Androgen Receptor). Cases and controls will be compared with respect to the prevalence of putative """"""""high risk"""""""" genotypes and alleles for each gene. The sample size also will provide sufficient statistical power to identify interaction between high-risk genotypes. The findings from this study therefore will add new information regarding the epidemiology and etiology of TGCC, and will serve as a resource for future investigations of genetic associations.

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National Cancer Institute (NCI)
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Epidemiology and Disease Control Subcommittee 2 (EDC)
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Verma, Mukesh
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Fred Hutchinson Cancer Research Center
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Biggs, Mary L; Doody, David R; Trabert, Britton et al. (2016) Consumption of alcoholic beverages in adolescence and adulthood and risk of testicular germ cell tumor. Int J Cancer 139:2405-14
Chung, Charles C; Kanetsky, Peter A; Wang, Zhaoming et al. (2013) Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet 45:680-5
Schumacher, Fredrick R; Wang, Zhaoming; Skotheim, Rolf I et al. (2013) Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23. Hum Mol Genet 22:2748-53
Kanetsky, Peter A; Mitra, Nandita; Vardhanabhuti, Saran et al. (2011) A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility. Hum Mol Genet 20:3109-17
Voigt, Lynda F; Schwartz, Stephen M; Doody, David R et al. (2011) Feasibility of including cellular telephone numbers in random digit dialing for epidemiologic case-control studies. Am J Epidemiol 173:118-26
Daling, Janet R; Doody, David R; Sun, Xiaofei et al. (2009) Association of marijuana use and the incidence of testicular germ cell tumors. Cancer 115:1215-23
Hsu, Li; Starr, Jacqueline R; Zheng, Yingye et al. (2009) On combining triads and unrelated subjects data in candidate gene studies: an application to data on testicular cancer. Hum Hered 67:88-103
Littman, Alyson J; Doody, David R; Biggs, Mary L et al. (2009) Physical activity in adolescence and testicular germ cell cancer risk. Cancer Causes Control 20:1281-90
Kanetsky, Peter A; Mitra, Nandita; Vardhanabhuti, Saran et al. (2009) Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet 41:811-5
Biggs, Mary L; Davis, Mark D; Eaton, David L et al. (2008) Serum organochlorine pesticide residues and risk of testicular germ cell carcinoma: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 17:2012-8

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