Grant Number:	1R01CA136621-01A1 Interpret this number
Primary Investigator:	Cooney, Kathleen
Organization:	University Of Michigan At Ann Arbor
Project Title:	Genome-Wide Scan for Genetic Variants Associated with Early-Onset Prostate Cancer
Fiscal Year:	2009

DESCRIPTION (provided by applicant): In 2008, prostate cancer (PCa) was the most commonly diagnosed cancer among men in the United States, with an estimated 186,320 new cases, and the second leading cause of cancer related mortality, with an estimated 28,660 related deaths. Identification of genes or other genomic variants that increase the susceptibility to PCa would impact public health by providing valuable biological data related to the development of PCa. PCa gene discoveries could additionally lead to novel treatment of PCa and provide a valuable additional screening tool for identification of men at increased risk for PCa. Men diagnosed with PCa at an early age are much more likely to die of the disease than men diagnosed later in life, and it has been shown that early-onset (EO) PCa is more likely due to genetic risk factors than later-onset disease. In this proposal, we describe an efficient and powerful multi-stage whole genome-wide association scan (GWAS) for genetic variants that are associated with EO PCa. In the first stage, we propose genotyping 1,000 Caucasian EO PCa cases from the University of Michigan (UM) on ~550,000 SNPs. Differences in observed allele frequencies between these UM EO PCa cases and >3,000 freely available controls from Illumina iControlDB will be assessed to identify a subset of SNPs for follow-up in the second stage. We will genotype the top 16,420 SNPs (plus 300 ancestry informative markers) identified from the first stage and from previous PCa GWASs on 1,250 Caucasian EO PCa cases and 1,000 screened controls from Johns Hopkins University (JHU). Finally, we will genotype, and test for association, our 1,236 most strongly associated SNPs from our second stage results (plus 300 ancestry informative markers) on a sample of 500 EO African American PCa cases and 500 African American controls from UM and JHU to assess the importance of our top findings in a second population that is disproportionably impacted by PCa. This study represents a powerful and unprecedented opportunity to identify genetic susceptibility variants that are associated with EO PCa using well-characterized samples from two investigative teams that have a long history of collaboration in PCa research. PUBLIC HEALTH RELEVANCE: In 2008, prostate cancer (PCa) was the most commonly diagnosed non-skin related cancer among men in the United States, with an estimated 186,320 new cases, and the second leading cause of cancer related mortality, with an estimated 28,660 related deaths. Identification of genes or other genomic variants that increase the susceptibility to PCa would impact public health by providing valuable biological data related to the development of PCa. This study represents a powerful and unprecedented opportunity to identify genetic susceptibility variants that are associated with EO PCa using two well-characterized samples.




Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer.
Authors: Lange E.M. , Ribado J.V. , Zuhlke K.A. , Johnson A.M. , Keele G.R. , Li J. , Wang Y. , Duan Q. , Li G. , Gao Z. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2016 05; 25(5), p. 766-72.
PMID: 26671023
Related Citations

The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies.
Authors: Beebe-Dimmer J.L. , Hathcock M. , Yee C. , Okoth L.A. , Ewing C.M. , Isaacs W.B. , Cooney K.A. , Thibodeau S.N. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2015 Sep; 24(9), p. 1366-72.
PMID: 26108461
Related Citations

Prostate cancer in young men: an important clinical entity.
Authors: Salinas C.A. , Tsodikov A. , Ishak-Howard M. , Cooney K.A. .
Source: Nature Reviews. Urology, 2014 Jun; 11(6), p. 317-23.
PMID: 24818853
Related Citations

Genome-wide association scan for variants associated with early-onset prostate cancer.
Authors: Lange E.M. , Johnson A.M. , Wang Y. , Zuhlke K.A. , Lu Y. , Ribado J.V. , Keele G.R. , Li J. , Duan Q. , Li G. , et al. .
Source: Plos One, 2014; 9(4), p. e93436.
PMID: 24740154
Related Citations

Elevated risk of prostate cancer among men with Lynch syndrome.
Authors: Raymond V.M. , Mukherjee B. , Wang F. , Huang S.C. , Stoffel E.M. , Kastrinos F. , Syngal S. , Cooney K.A. , Gruber S.B. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2013-05-10 00:00:00.0; 31(14), p. 1713-8.
EPub date: 2013-05-10 00:00:00.0.
PMID: 23530095
Related Citations

Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy.
Authors: Schroeck F.R. , Zuhlke K.A. , Siddiqui J. , Siddiqui R. , Cooney K.A. , Wei J.T. .
Source: The Journal Of Urology, 2013 Mar; 189(3), p. 849-53.
PMID: 23036981
Related Citations

HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).
Authors: Xu J. , Lange E.M. , Lu L. , Zheng S.L. , Wang Z. , Thibodeau S.N. , Cannon-Albright L.A. , Teerlink C.C. , Camp N.J. , Johnson A.M. , et al. .
Source: Human Genetics, 2013 Jan; 132(1), p. 5-14.
PMID: 23064873
Related Citations

Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer.
Authors: Zuhlke K.A. , Johnson A.M. , Okoth L.A. , Stoffel E.M. , Robbins C.M. , Tembe W.A. , Salinas C.A. , Zheng S.L. , Xu J. , Carpten J.D. , et al. .
Source: Familial Cancer, 2012 Dec; 11(4), p. 595-600.
PMID: 22864661
Related Citations

Early onset prostate cancer has a significant genetic component.
Authors: Lange E.M. , Salinas C.A. , Zuhlke K.A. , Ray A.M. , Wang Y. , Lu Y. , Ho L.A. , Luo J. , Cooney K.A. .
Source: The Prostate, 2012-02-01 00:00:00.0; 72(2), p. 147-56.
EPub date: 2012-02-01 00:00:00.0.
PMID: 21538423
Related Citations

Germline mutations in HOXB13 and prostate-cancer risk.
Authors: Ewing C.M. , Ray A.M. , Lange E.M. , Zuhlke K.A. , Robbins C.M. , Tembe W.D. , Wiley K.E. , Isaacs S.D. , Johng D. , Wang Y. , et al. .
Source: The New England Journal Of Medicine, 2012-01-12 00:00:00.0; 366(2), p. 141-9.
PMID: 22236224
Related Citations

National Cancer Institute Prostate Cancer Genetics Workshop.
Authors: Catalona W.J. , Bailey-Wilson J.E. , Camp N.J. , Chanock S.J. , Cooney K.A. , Easton D.F. , Eeles R.A. , FitzGerald L.M. , Freedman M.L. , Gudmundsson J. , et al. .
Source: Cancer Research, 2011-05-15 00:00:00.0; 71(10), p. 3442-6.
EPub date: 2011-05-15 00:00:00.0.
PMID: 21558387
Related Citations

Using public control genotype data to increase power and decrease cost of case-control genetic association studies.
Authors: Ho L.A. , Lange E.M. .
Source: Human Genetics, 2010 Dec; 128(6), p. 597-608.
PMID: 20821337
Related Citations