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Grant Details

Grant Number: 3R01CA085074-09S1 Interpret this number
Primary Investigator: Rebbeck, Timothy
Organization: University Of Pennsylvania
Project Title: Ethnic Difference in Prostate Cancer
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly occurring cancer in men of African descent in the U.S. Even though African American men have the highest prostate cancer rate in the world, there is relatively little information available about the etiologic factors that may explain these rates. Despite the knowledge that prostate cancer occurs at high rates in men of African descent in the Americas, very little data is available regarding the epidemiology of prostate cancer in native African men, even though prostate cancer seems to be prevalent in that population. We hypothesize that a better understanding of prostate cancer risk in African men could elucidate factors affecting the high incidence of prostate cancer in African American men. The objective of the present study is to examine the role of genes that regulate the disposition of testosterone in prostate cancer etiology in men of African descent, and to evaluate whether these genes explain, in part, ethnic differences in prostate cancer rates. These genes include the cytochromes P450 CYP3A4, CYP3A5, CYP3A43, and CYP19, 5alpha-reductase II (SRD5A2), androgen receptor (AR), and the hydroxy-steroid dehydrogenases type II 3beta (HSD3B) and type 17beta (HSD17B). These genes are involved in testosterone metabolism, and thus focus our hypotheses on a relevant, defined set of metabolic pathways. Three specific aims are proposed here. In Specific Aim 1, we will use publicly available databases to evaluate genetic variation at candidate androgen metabolism genes in African American and Senegalese population, including SNP characterization, identification of haplotype tag SNPs (htSNPs) and haplotypes, as well as characterization of linkage disequilibrium blocks. In Specific Aim 2. we will characterize population genetic structure in African American and Senegalese men using genomic markers, and use this information to assess the potential for population stratification in African and African American populations. In Specific Aim 3, we will assess the relationship of genetic variability in case-control analyses of prostate cancer in Africans and African Americans using haplotypes and multivariate genotypes. In order to address these aims in this competing continuation proposal, we will build on our existing epidemiological participant accrual and data management infrastructure that has been developed under previously funded grants (R01-CA85074 to Dr. Rebbeck and R03-CA103359 to Dr. Gueye). Using this previous funding, we have developed comprehensive and comparable protocols for the identification of incident prostate cancer cases and controls in Philadelphia and Dakar. At both locations, risk factor information is obtained from a questionnaire interview, a biosample containing DNA is collected using a non-invasive cheek swab method, and pathology information is collected using a standardized medical record abstraction approach. The resources and data generated through this proposal will be used to determine the role of genes and other risk factors in prostate cancer etiology. An understanding of the complex interplay of genetic variability at multiple loci as well as other factors may improve our understanding of ethnic differences in prostate cancer etiology and risk prediction, and in particular help us to understand why African American men have the highest rates of prostate cancer incidence in the world.

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Publications

Relationship of early-onset baldness to prostate cancer in African-American men.
Authors: Zeigler-Johnson C, Morales KH, Spangler E, Chang BL, Rebbeck TR
Source: Cancer Epidemiol Biomarkers Prev, 2013 Apr;22(4), p. 589-96.
EPub date: 2013 Mar 26.
PMID: 23532004
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Bridging the gap between biologic, individual, and macroenvironmental factors in cancer: a multilevel approach.
Authors: Lynch SM, Rebbeck TR
Source: Cancer Epidemiol Biomarkers Prev, 2013 Apr;22(4), p. 485-95.
EPub date: 2013 Mar 5.
PMID: 23462925
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Relationship of obesity, androgen receptor genotypes and biochemical failure after radical prostatectomy.
Authors: Zeigler-Johnson C, Weber A, Spangler E, Panossian S, Rebbeck TR, Malkowicz SB
Source: Prostate, 2012 Jun 15;72(9), p. 984-90.
EPub date: 2011 Oct 24.
PMID: 22025404
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Dissecting the within-Africa ancestry of populations of African descent in the Americas.
Authors: Stefflova K, Dulik MC, Barnholtz-Sloan JS, Pai AA, Walker AH, Rebbeck TR
Source: PLoS One, 2011 Jan 6;6(1), p. e14495.
EPub date: 2011 Jan 6.
PMID: 21253579
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Context-dependent effects of genome-wide association study genotypes and macroenvironment on time to biochemical (prostate specific antigen) failure after prostatectomy.
Authors: Rebbeck TR, Weber AL, Walker AH, Stefflova K, Tran TV, Spangler E, Chang BL, Zeigler-Johnson CM
Source: Cancer Epidemiol Biomarkers Prev, 2010 Sep;19(9), p. 2115-23.
PMID: 20826827
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Evaluation of group genetic ancestry of populations from Philadelphia and Dakar in the context of sex-biased admixture in the Americas.
Authors: Stefflova K, Dulik MC, Pai AA, Walker AH, Zeigler-Johnson CM, Gueye SM, Schurr TG, Rebbeck TR
Source: PLoS One, 2009 Nov 25;4(11), p. e7842.
EPub date: 2009 Nov 25.
PMID: 19946364
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Evaluation of prostate cancer characteristics in four populations worldwide.
Authors: Zeigler-Johnson CM, Rennert H, Mittal RD, Jalloh M, Sachdeva R, Malkowicz SB, Mandhani A, Mittal B, Gueye SM, Rebbeck TR
Source: Can J Urol, 2008 Jun;15(3), p. 4056-64.
PMID: 18570709
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Joint effects of inflammation and androgen metabolism on prostate cancer severity.
Authors: Rebbeck TR, Rennert H, Walker AH, Panossian S, Tran T, Walker K, Spangler E, Patacsil-Coomes M, Sachdeva R, Wein AJ, Malkowicz SB, Zeigler-Johnson C
Source: Int J Cancer, 2008 Sep 15;123(6), p. 1385-9.
PMID: 18566991
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Genetic susceptibility to prostate cancer in men of African descent: implications for global disparities in incidence and outcomes.
Authors: Zeigler-Johnson CM, Spangler E, Jalloh M, Gueye SM, Rennert H, Rebbeck TR
Source: Can J Urol, 2008 Feb;15(1), p. 3872-82.
PMID: 18304397
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Association of obesity with tumor characteristics and treatment failure of prostate cancer in African-American and European American men.
Authors: Spangler E, Zeigler-Johnson CM, Coomes M, Malkowicz SB, Wein A, Rebbeck TR
Source: J Urol, 2007 Nov;178(5), p. 1939-44; discussion 1945.
EPub date: 2007 Sep 17.
PMID: 17868722
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Evaluating bias due to population stratification in epidemiologic studies of gene-gene or gene-environment interactions.
Authors: Wang Y, Localio R, Rebbeck TR
Source: Cancer Epidemiol Biomarkers Prev, 2006 Jan;15(1), p. 124-32.
PMID: 16434597
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Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men.
Authors: Rennert H, Zeigler-Johnson CM, Addya K, Finley MJ, Walker AH, Spangler E, Leonard DG, Wein A, Malkowicz SB, Rebbeck TR
Source: Cancer Epidemiol Biomarkers Prev, 2005 Apr;14(4), p. 949-57.
PMID: 15824169
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CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer.
Authors: Zeigler-Johnson C, Friebel T, Walker AH, Wang Y, Spangler E, Panossian S, Patacsil M, Aplenc R, Wein AJ, Malkowicz SB, Rebbeck TR
Source: Cancer Res, 2004 Nov 15;64(22), p. 8461-7.
PMID: 15548719
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Association of prostate cancer family history with histopathological and clinical characteristics of prostate tumors.
Authors: Spangler E, Zeigler-Johnson CM, Malkowicz SB, Wein AJ, Rebbeck TR
Source: Int J Cancer, 2005 Jan 20;113(3), p. 471-4.
PMID: 15455347
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Clinical characteristics of prostate cancer in African Americans, American whites, and Senegalese men.
Authors: Gueye SM, Zeigler-Johnson CM, Friebel T, Spangler E, Jalloh M, MacBride S, Malkowicz SB, Rebbeck TR
Source: Urology, 2003 May;61(5), p. 987-92.
PMID: 12736021
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Group sequential methods and sample size savings in biomarker-disease association studies.
Authors: Aplenc R, Zhao H, Rebbeck TR, Propert KJ
Source: Genetics, 2003 Mar;163(3), p. 1215-9.
PMID: 12663557
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Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4.
Authors: Zeigler-Johnson CM, Walker AH, Mancke B, Spangler E, Jalloh M, McBride S, Deitz A, Malkowicz SB, Ofori-Adjei D, Gueye SM, Rebbeck TR
Source: Hum Hered, 2002;54(1), p. 13-21.
PMID: 12446983
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Inherited genotype and prostate cancer outcomes.
Authors: Rebbeck TR
Source: Cancer Epidemiol Biomarkers Prev, 2002 Oct;11(10 Pt 1), p. 945-52.
PMID: 12376492
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The glutathione S-transferase-mu and -theta genotypes in the etiology of prostate cancer: genotype-environment interactions with smoking.
Authors: Kelada SN, Kardia SL, Walker AH, Wein AJ, Malkowicz SB, Rebbeck TR
Source: Cancer Epidemiol Biomarkers Prev, 2000 Dec;9(12), p. 1329-34.
PMID: 11142418
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Association of HPC2/ELAC2 genotypes and prostate cancer.
Authors: Rebbeck TR, Walker AH, Zeigler-Johnson C, Weisburg S, Martin AM, Nathanson KL, Wein AJ, Malkowicz SB
Source: Am J Hum Genet, 2000 Oct;67(4), p. 1014-9.
EPub date: 2000 Sep 12.
PMID: 10986046
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Association of SRD5A2 genotype and pathological characteristics of prostate tumors.
Authors: Jaffe JM, Malkowicz SB, Walker AH, MacBride S, Peschel R, Tomaszewski J, Van Arsdalen K, Wein AJ, Rebbeck TR
Source: Cancer Res, 2000 Mar 15;60(6), p. 1626-30.
PMID: 10749132
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