Prostate cancer is one of the leading causes of morbidity and mortality among men. We do not have an understanding of the underlying etiology of prostate cancer, or why different groups such as African Americans have higher rates of this disease. Risk factors for prostate cancer have remained elusive, other than age, having a family history of the disease and African ancestry, until recently with the discovery of multiple disease risk loci utilizing Genome Wide Association Studies( GWAS ). The first such loci were discovered in a gene """""""" desert """""""" in 8q24, and now the total number of loci number at least 30. Many of the allelic loci identified since those in 8q24, lie within introns or nearby known gene regions. Given the SNP density of the current tools used for GWAS, virtually all the risk loci identified have been found to be common allelic variants and the relative risk of prostate cancer from each such risk locus tends to be modest, e.g. 1.1-1.3. While differences in the frequency of such individual risk alleles, particularly in the 8q24 region, can partially account for the higher risk in populations of African ancestry, all the risk loci detected to date account for no more than 20-25% of the familial risk of prostate cancer. It has been hypothesized that less common or rare functional risk alleles might be identifiable in those loci located within or near to known functional candidate gene regions, and that such less common or rare alleles might explain both the """""""" signal """""""" identified by a more common allele in LD and a somewhat greater familial and/ or population attributable risk. In this application we have assembled a multi- institutional team of investigators with experience in prostate cancer research in minority populations who are willing to pool resources for a large scale attempt to identify such less common or rare alleles. We propose to collaborate with David Reich at Harvard who has the capability to bar code and pool large numbers of DNA samples for deep sequencing across the risk regions where the common allelic variants have been discovered. To optimize our ability to identify these less common and rare variants we propose to include 4500 prostate cases and controls from the Multiethnic Cohort ( Japanese, African American, European American, Latino and Native Hawaiian ) as well as 500 African American prostate cancer cases with a family history of prostate cancer from among those populations currently participating in the collaborative GWAS of African Americans being conducted at USC. We expect this effort to significantly advance knowledge of the genetic risk factors for sporadic and familial prostate cancer among a variety of different racial/ethnic groups, including the highest risk population of African ancestry. The specific identification of the functional genetic variants in the risk loci that have been discovered by GWAS should guide the development of future preventive, early detection, prognostic and even therapeutic measures.

Public Health Relevance

The goal of this project is to identify less common and rare risk alleles for prostate cancer in the approximately 30 allelic loci that have been discovered by genome wide association studies. For this effort, we will utilize the resources of the Multiethnic Cohort Study populations (African American, Japanese, Latino, European American, and Native Hawaiian) as well as several of the key populations of African Americans who are part of the funded African American prostate cancer genome wide association study. More specifically we propose to sequence 4500 individuals with prostate cancer and 4500 controls from the Multiethnic Cohort Study and an additional 500 African American prostate cancer cases with a family history of prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Martin, Damali
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Public Health & Prev Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Gong, J; Nishimura, K K; Fernandez-Rhodes, L et al. (2018) Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI. Int J Obes (Lond) 42:384-390
Silvestrov, Pavel; Maier, Sarah J; Fang, Michelle et al. (2018) DNArCdb: A database of cancer biomarkers in DNA repair genes that includes variants related to multiple cancer phenotypes. DNA Repair (Amst) 70:10-17
Kocarnik, Jonathan M; Richard, Melissa; Graff, Misa et al. (2018) Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study. Hum Mol Genet 27:2940-2953
Fernández-Rhodes, Lindsay; Malinowski, Jennifer R; Wang, Yujie et al. (2018) The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis. PLoS One 13:e0200486
Bien, Stephanie A; Pankow, James S; Haessler, Jeffrey et al. (2017) Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Diabetologia 60:2384-2398
Justice, Anne E (see original citation for additional authors) (2017) Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits. Nat Commun 8:14977
Yoneyama, S; Yao, J; Guo, X et al. (2017) Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations. Int J Obes (Lond) 41:324-331
Wang, Hansong; Schmit, Stephanie L; Haiman, Christopher A et al. (2017) Novel colon cancer susceptibility variants identified from a genome-wide association study in African Americans. Int J Cancer 140:2728-2733
Walker, Alice R; Silvestrov, Pavel; Müller, Tina A et al. (2017) ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding. PLoS Comput Biol 13:e1005345
Johnson, Eric O; Hancock, Dana B; Levy, Joshua L et al. (2016) KAT2B polymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex. Addict Biol 21:1217-1232

Showing the most recent 10 out of 56 publications