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.
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.
|Lange, Ethan M; Ribado, Jessica V; Zuhlke, Kimberly A et al. (2016) Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer. Cancer Epidemiol Biomarkers Prev 25:766-72|
|Beebe-Dimmer, Jennifer L; Hathcock, Matthew; Yee, Cecilia et al. (2015) The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies. Cancer Epidemiol Biomarkers Prev 24:1366-72|
|Lange, Ethan M; Johnson, Anna M; Wang, Yunfei et al. (2014) Genome-wide association scan for variants associated with early-onset prostate cancer. PLoS One 9:e93436|
|Salinas, Claudia A; Tsodikov, Alex; Ishak-Howard, Miriam et al. (2014) Prostate cancer in young men: an important clinical entity. Nat Rev Urol 11:317-23|
|Xu, Jianfeng; Lange, Ethan M; Lu, Lingyi et al. (2013) HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum Genet 132:5-14|
|Raymond, Victoria M; Mukherjee, Bhramar; Wang, Fei et al. (2013) Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 31:1713-8|
|Schroeck, Florian R; Zuhlke, Kimberly A; Siddiqui, Javed et al. (2013) Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy. J Urol 189:849-53|
|Zuhlke, Kimberly A; Johnson, Anna M; Okoth, Linda A et al. (2012) Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer. Fam Cancer 11:595-600|
|Lange, Ethan M; Salinas, Claudia A; Zuhlke, Kimberly A et al. (2012) Early onset prostate cancer has a significant genetic component. Prostate 72:147-56|
|Ewing, Charles M; Ray, Anna M; Lange, Ethan M et al. (2012) Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 366:141-9|
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