Testicular germ cell tumors (TGCT) are the most common cancer in men ages 20-40. The incidence of TGCT has more than doubled over the past forty years, without clear etiology. Both genetic effects and environmental exposures, specifically during the pre-natal period, are likely to play an important role in determining TGCT susceptibility. TGCT is known to develop from primordial germ cells (PGCs). We hypothesize that variation in genes that impact upon the differentiation and maturation of PGCs will be important determinants of TGCT susceptibility and based on this hypothesis have selected three important pathways for study, i) male germ cell development, ii) androgen and estrogen biosynthesis and metabolism, and iii) IGF signaling. The proteins involved in early male germ cell development, normally only expressed in PGCs, are markers of and are overexpressed in TGCT. Markers of increased exposure to estrogen (or relatively decreased exposure to androgen) in utero and exogenous estrogen exposures, such as endocrine disrupters, have been associated with TGCT case status in multiple studies. IGF signaling is necessary for testis differentiation and maturation in mice and interacts synergistically with the estrogen signaling pathway. We will analyze the contribution of genetic variants in these pathways to TGCT risk using a population-based case-control study in the Philadelphia metropolitan area. Our goal is the collection of 550 TGCT cases and 1100 age, race and cell phone use matched controls without a history of TGCT, which will yield 500 and 1000 white cases and controls, respectively, available for final analyses. All cases will be enumerated through the New Jersey and Pennsylvania state cancer registries. We will use a two-tiered approach for case recruitment: hospital clinic-based followed by registry-based. Controls will be identified through random digit dialing. Both cases and controls will complete a questionnaire addressing known, presumed, and hypothesized risk factors for TGCT and provide a blood sample or buccal swab. Pathological slides will be reviewed to cases to confirm diagnostic sub-type of TGCT. Haplotypes and functional SNPs will be typed in the genes of interest. Analyses will be conducted for specific variants, common haplotypes, alone and in conjunction with each other and exposure data after appropriate adjustment for potential confounders. The findings from this study will greatly contribute to our understanding of determinants of TGCT susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114478-05
Application #
8116451
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Zanetti, Krista A
Project Start
2007-09-01
Project End
2013-06-30
Budget Start
2011-07-18
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$529,388
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pyle, Louise C; Nathanson, Katherine L (2017) A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development. Am J Med Genet C Semin Med Genet 175:304-314
Wang, Zhaoming; McGlynn, Katherine A; Rajpert-De Meyts, Ewa et al. (2017) Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor. Nat Genet 49:1141-1147
Pyle, Louise C; Nathanson, Katherine L (2016) Genetic changes associated with testicular cancer susceptibility. Semin Oncol 43:575-581
Clagett, Bartholt; Nathanson, Katherine L; Ciosek, Stephanie L et al. (2013) Comparison of address-based sampling and random-digit dialing methods for recruiting young men as controls in a case-control study of testicular cancer susceptibility. Am J Epidemiol 178:1638-47
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
Maxwell, Kara N; Nathanson, Katherine L (2013) Common breast cancer risk variants in the post-COGS era: a comprehensive review. Breast Cancer Res 15:212
Sabbaghian, Nelly; Bahubeshi, Amin; Shuen, Andrew Y et al. (2013) Germ-line DICER1 mutations do not make a major contribution to the etiology of familial testicular germ cell tumours. BMC Res Notes 6:127
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
Crino, Peter B; Aronica, Eleonora; Baltuch, Gordon et al. (2010) Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 74:1716-23

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