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Grant Details

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
Fiscal Year: 2011
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Abstract

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.

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Publications

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 CC, Wang Z, Loren Erickson R, Vaughn DJ, Litchfield K, Rahman N, Greene MH, McGlynn KA, Turnbull C, Chanock SJ, Nathanson KL, Kanetsky PA
Source: Hum Mol Genet, 2014 Nov 15;23(22), p. 6061-8.
EPub date: 2014 Jun 18.
PMID: 24943593
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Common breast cancer risk variants in the post-COGS era: a comprehensive review.
Authors: Maxwell KN, Nathanson KL
Source: Breast Cancer Res, 2013 Dec 20;15(6), p. 212.
EPub date: 2013 Dec 20.
PMID: 24359602
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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 KL, Ciosek SL, McDermoth M, Vaughn DJ, Mitra N, Weiss A, Martonik R, Kanetsky PA
Source: Am J Epidemiol, 2013 Dec 1;178(11), p. 1638-47.
EPub date: 2013 Sep 5.
PMID: 24008901
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Meta-analysis identifies four new loci associated with testicular germ cell tumor.
Authors: Chung CC, Kanetsky PA, Wang Z, Hildebrandt MA, Koster R, Skotheim RI, Kratz CP, Turnbull C, Cortessis VK, Bakken AC, Bishop DT, Cook MB, Erickson RL, Fosså SD, Jacobs KB, Korde LA, Kraggerud SM, Lothe RA, Loud JT, Rahman N, Skinner EC, Thomas DC, Wu X, Yeager M, Schumacher FR, Greene MH, Schwartz SM, McGlynn KA, Chanock SJ, Nathanson KL
Source: Nat Genet, 2013 Jun;45(6), p. 680-5.
EPub date: 2013 May 12.
PMID: 23666239
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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 AY, Kanetsky PA, Tischkowitz MD, Nathanson KL, Foulkes WD
Source: BMC Res Notes, 2013 Apr 1;6, p. 127.
EPub date: 2013 Apr 1.
PMID: 23547758
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Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.
Authors: Schumacher FR, Wang Z, Skotheim RI, Koster R, Chung CC, Hildebrandt MA, Kratz CP, Bakken AC, Bishop DT, Cook MB, Erickson RL, Fosså SD, Greene MH, Jacobs KB, Kanetsky PA, Kolonel LN, Loud JT, Korde LA, Le Marchand L, Lewinger JP, Lothe RA, Pike MC, Rahman N, Rubertone MV, Schwartz SM, Siegmund KD, Skinner EC, Turnbull C, Van Den Berg DJ, Wu X, Yeager M, Nathanson KL, Chanock SJ, Cortessis VK, McGlynn KA
Source: Hum Mol Genet, 2013 Jul 1;22(13), p. 2748-53.
EPub date: 2013 Mar 5.
PMID: 23462292
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A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.
Authors: Kanetsky PA, Mitra N, Vardhanabhuti S, Vaughn DJ, Li M, Ciosek SL, Letrero R, D'Andrea K, Vaddi M, Doody DR, Weaver J, Chen C, Starr JR, Håkonarson H, Rader DJ, Godwin AK, Reilly MP, Schwartz SM, Nathanson KL
Source: Hum Mol Genet, 2011 Aug 1;20(15), p. 3109-17.
EPub date: 2011 May 6.
PMID: 21551455
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Biallelic TSC gene inactivation in tuberous sclerosis complex.
Authors: Crino PB, Aronica E, Baltuch G, Nathanson KL
Source: Neurology, 2010 May 25;74(21), p. 1716-23.
PMID: 20498439
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Using genetics and genomics strategies to personalize therapy for cancer: focus on melanoma.
Authors: Nathanson KL
Source: Biochem Pharmacol, 2010 Sep 1;80(5), p. 755-61.
EPub date: 2010 Apr 20.
PMID: 20412787
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Predisposition alleles for Testicular Germ Cell Tumour.
Authors: Rapley EA, Nathanson KL
Source: Curr Opin Genet Dev, 2010 Jun;20(3), p. 225-30.
EPub date: 2010 Mar 19.
PMID: 20303738
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Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer.
Authors: Kanetsky PA, Mitra N, Vardhanabhuti S, Li M, Vaughn DJ, Letrero R, Ciosek SL, Doody DR, Smith LM, Weaver J, Albano A, Chen C, Starr JR, Rader DJ, Godwin AK, Reilly MP, Hakonarson H, Schwartz SM, Nathanson KL
Source: Nat Genet, 2009 Jul;41(7), p. 811-5.
EPub date: 2009 May 31.
PMID: 19483682
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The International Testicular Cancer Linkage Consortium: a clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindred.
Authors: Mai PL, Friedlander M, Tucker K, Phillips KA, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Bonaïti-Pellié C, Heidenreich A, Albers P, Bodrogi I, Geczi L, Olah E, Daly PA, Guilford P, Fosså SD, Heimdal K, Liubchenko L, Tjulandin SA, Stoll H, Weber W, Easton DF, Dudakia D, Huddart R, Stratton MR, Einhorn L, Korde L, Nathanson KL, Bishop DT, Rapley EA, Greene MH
Source: Urol Oncol, 2010 Sep-Oct;28(5), p. 492-9.
EPub date: 2009 Jan 22.
PMID: 19162511
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