|Grant Number:||5R01CA114478-05 Interpret this number|
|Primary Investigator:||Nathanson, Katherine|
|Organization:||University Of Pennsylvania|
|Project Title:||Inherited Genetic Variation and Predisposition to Testicular Germ Cell Tumor|
DESCRIPTION (provided by applicant): 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.
Pathway-based Analysis Of Gwas Data Identifies Association Of Sex Determination Genes With Susceptibility To Testicular Germ Cell Tumors
Authors: Koster R. , Mitra N. , D'Andrea K. , Vardhanabhuti S. , Chung C.C. , Wang Z. , Loren Erickson R. , Vaughn D.J. , Litchfield K. , Rahman N. , et al. .
Source: Human Molecular Genetics, 2014-11-15 00:00:00.0; 23(22), p. 6061-8.
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
Authors: Clagett B. , Nathanson K.L. , Ciosek S.L. , McDermoth M. , Vaughn D.J. , Mitra N. , Weiss A. , Martonik R. , Kanetsky P.A. .
Source: American Journal Of Epidemiology, 2013-12-01 00:00:00.0; 178(11), p. 1638-47.
Testicular Germ Cell Tumor Susceptibility Associated With The Uck2 Locus On Chromosome 1q23
Authors: Schumacher F.R. , Wang Z. , Skotheim R.I. , Koster R. , Chung C.C. , Hildebrandt M.A. , Kratz C.P. , Bakken A.C. , Bishop D.T. , Cook M.B. , et al. .
Source: Human Molecular Genetics, 2013-07-01 00:00:00.0; 22(13), p. 2748-53.
Meta-analysis Identifies Four New Loci Associated With Testicular Germ Cell Tumor
Authors: Chung C.C. , Kanetsky P.A. , Wang Z. , Hildebrandt M.A. , Koster R. , Skotheim R.I. , Kratz C.P. , Turnbull C. , Cortessis V.K. , Bakken A.C. , et al. .
Source: Nature Genetics, 2013 Jun; 45(6), p. 680-5.
Germ-line Dicer1 Mutations Do Not Make A Major Contribution To The Etiology Of Familial Testicular Germ Cell Tumours
Authors: Sabbaghian N. , Bahubeshi A. , Shuen A.Y. , Kanetsky P.A. , Tischkowitz M.D. , Nathanson K.L. , Foulkes W.D. .
Source: Bmc Research Notes, 2013; 6, p. 127.
Common Breast Cancer Risk Variants In The Post-cogs Era: A Comprehensive Review
Authors: Maxwell K.N. , Nathanson K.L. .
Source: Breast Cancer Research : Bcr, 2013; 15(6), p. 212.
A Second Independent Locus Within Dmrt1 Is Associated With Testicular Germ Cell Tumor Susceptibility
Authors: Kanetsky P.A. , Mitra N. , Vardhanabhuti S. , Vaughn D.J. , Li M. , Ciosek S.L. , Letrero R. , D'Andrea K. , Vaddi M. , Doody D.R. , et al. .
Source: Human Molecular Genetics, 2011-08-01 00:00:00.0; 20(15), p. 3109-17.
The International Testicular Cancer Linkage Consortium: A Clinicopathologic Descriptive Analysis Of 461 Familial Malignant Testicular Germ Cell Tumor Kindred
Authors: Mai P.L. , Friedlander M. , Tucker K. , Phillips K.A. , Hogg D. , Jewett M.A. , Lohynska R. , Daugaard G. , Richard S. , Bonaïti-Pellié C. , et al. .
Source: Urologic Oncology, 2010 Sep-Oct; 28(5), p. 492-9.
Using Genetics And Genomics Strategies To Personalize Therapy For Cancer: Focus On Melanoma
Authors: Nathanson K.L. .
Source: Biochemical Pharmacology, 2010-09-01 00:00:00.0; 80(5), p. 755-61.
Predisposition Alleles For Testicular Germ Cell Tumour
Authors: Rapley E.A. , Nathanson K.L. .
Source: Current Opinion In Genetics & Development, 2010 Jun; 20(3), p. 225-30.
Biallelic Tsc Gene Inactivation In Tuberous Sclerosis Complex
Authors: Crino P.B. , Aronica E. , Baltuch G. , Nathanson K.L. .
Source: Neurology, 2010-05-25 00:00:00.0; 74(21), p. 1716-23.
Common Variation In Kitlg And At 5q31.3 Predisposes To Testicular Germ Cell Cancer
Authors: Kanetsky P.A. , Mitra N. , Vardhanabhuti S. , Li M. , Vaughn D.J. , Letrero R. , Ciosek S.L. , Doody D.R. , Smith L.M. , Weaver J. , et al. .
Source: Nature Genetics, 2009 Jul; 41(7), p. 811-5.