|Grant Number:||5R01CA136621-04 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|
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.
Elevated risk of prostate cancer among men with Lynch syndrome.
Authors: Raymond VM, Mukherjee B, Wang F, Huang SC, Stoffel EM, Kastrinos F, Syngal S, Cooney KA, Gruber SB
Source: J Clin Oncol, 2013 May 10;31(14), p. 1713-8.
EPub date: 2013 Mar 25.
HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).
Authors: Xu J, Lange EM, Lu L, Zheng SL, Wang Z, Thibodeau SN, Cannon-Albright LA, Teerlink CC, Camp NJ, Johnson AM, Zuhlke KA, Stanford JL, Ostrander EA, Wiley KE, Isaacs SD, Walsh PC, Maier C, Luedeke M, Vogel W, Schleutker J, Wahlfors T, Tammela T, Schaid D, McDonnell SK, DeRycke MS, Cancel-Tassin G, Cussenot O, Wiklund F, Grönberg H, Eeles R, Easton D, Kote-Jarai Z, Whittemore AS, Hsieh CL, Giles GG, Hopper JL, Severi G, Catalona WJ, Mandal D, Ledet E, Foulkes WD, Hamel N, Mahle L, Moller P, Powell I, Bailey-Wilson JE, Carpten JD, Seminara D, Cooney KA, Isaacs WB, International Consortium for Prostate Cancer Genetics
Source: Hum Genet, 2013 Jan;132(1), p. 5-14.
EPub date: 2012 Oct 12.
Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy.
Authors: Schroeck FR, Zuhlke KA, Siddiqui J, Siddiqui R, Cooney KA, Wei JT
Source: J Urol, 2013 Mar;189(3), p. 849-53.
EPub date: 2012 Oct 2.
Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer.
Authors: Zuhlke KA, Johnson AM, Okoth LA, Stoffel EM, Robbins CM, Tembe WA, Salinas CA, Zheng SL, Xu J, Carpten JD, Lange EM, Isaacs WB, Cooney KA
Source: Fam Cancer, 2012 Dec;11(4), p. 595-600.
Germline mutations in HOXB13 and prostate-cancer risk.
Authors: Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD, Wiley KE, Isaacs SD, Johng D, Wang Y, Bizon C, Yan G, Gielzak M, Partin AW, Shanmugam V, Izatt T, Sinari S, Craig DW, Zheng SL, Walsh PC, Montie JE, Xu J, Carpten JD, Isaacs WB, Cooney KA
Source: N Engl J Med, 2012 Jan 12;366(2), p. 141-9.
National Cancer Institute Prostate Cancer Genetics Workshop.
Authors: Catalona WJ, Bailey-Wilson JE, Camp NJ, Chanock SJ, Cooney KA, Easton DF, Eeles RA, FitzGerald LM, Freedman ML, Gudmundsson J, Kittles RA, Margulies EH, McGuire BB, Ostrander EA, Rebbeck TR, Stanford JL, Thibodeau SN, Witte JS, Isaacs WB
Source: Cancer Res, 2011 May 15;71(10), p. 3442-6.
EPub date: 2011 May 10.
Early onset prostate cancer has a significant genetic component.
Authors: Lange EM, Salinas CA, Zuhlke KA, Ray AM, Wang Y, Lu Y, Ho LA, Luo J, Cooney KA
Source: Prostate, 2012 Feb 1;72(2), p. 147-56.
EPub date: 2011 May 2.
Using public control genotype data to increase power and decrease cost of case-control genetic association studies.
Authors: Ho LA, Lange EM
Source: Hum Genet, 2010 Dec;128(6), p. 597-608.
EPub date: 2010 Sep 7.