The morbidity and mortality due to prostate cancer varies substantially across ethnic groups, and there is clear evidence that genetic factors impact a man's risk of prostate cancer. However, finding genetic variants that cause this common but complex disease has proven difficult. Traditional genome-wide linkage and candidate gene studies have produced equivocal results. This is due in part to the reduced power of linkage studies to detect common variants with modest effects and the limited number of genes evaluated in candidate gene studies. A more promising approach is to search for prostate cancer causing genetic variants using a genome- wide association study of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Recent GWAs of prostate cancer focused on Caucasians have detected a number of extremely promising associations. We propose building on these exciting results with large a genome-wide association study of how SNPs and CNVs impact prostate cancer risk in minority populations. Specifically, we will study 2,000 prostate cancer cases and 2,000 age and ethnicity matched controls (2,000 African-Americans, and 2,000 Asian-Americans) nested in the Northern California Kaiser Permanente population.
Our first aim i s to obtain biospecimens on this nested case-control population. Second, we will genotype the new Affymetrix SNP Array 6.0 on the entire study population. This single-stage design is highly efficient in light of the rapidly decreasing genotyping costs, and is necessary to fully evaluate both SNPs and CNVs.
Our third aim will investigate the association between the SNPs measured by the Array and prostate cancer. Fourth, we will determine CNVs from the Array, and evaluate how they effect prostate cancer risk (i.e., alone and in conjunction with the SNPs). The study sample size of 4,000 subjects and the comprehensive SNP Array 6.0 information provide sufficient power for detecting SNP and CNV associations with prostate cancer. By focusing this genome-wide association study on the two ethnic groups with the highest and lowest risks of prostate cancer and studying subjects from the highly representative Kaiser Permanente population this project provides an outstanding opportunity to determine the genetic causes of this disease in understudied populations. Finding such genetic factors will have substantial significance with regard to improving screening, treatment modalities, and understanding the biologic basis of prostate cancer.

Public Health Relevance

Prostate cancer is one of the most common and clearly familial / genetic cancers, but finding the cause of this disease has proven extremely difficult. Our efforts toward deciphering the genetic basis of prostate cancer in minority populations will help improve screening, treatment, and our overall understanding of this disease. These advances will improve the overall health of men, providing much needed information about individual- and population-level risks of prostate cancer within understudied populations.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-HOP-T (05))
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Seminara, Daniela
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University of California San Francisco
Public Health & Prev Medicine
Schools of Medicine
San Francisco
United States
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Han, Ying; Signorello, Lisa B; Strom, Sara S et al. (2015) Generalizability of established prostate cancer risk variants in men of African ancestry. Int J Cancer 136:1210-7
Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I et al. (2014) A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 46:1103-9
Witte, John S; Visscher, Peter M; Wray, Naomi R (2014) The contribution of genetic variants to disease depends on the ruler. Nat Rev Genet 15:765-76
Monda, Keri L; Chen, Gary K; Taylor, Kira C et al. (2013) A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nat Genet 45:690-6
Witte, John S; Mefford, Joel; Plummer, Sarah J et al. (2013) HOXB13 mutation and prostate cancer: studies of siblings and aggressive disease. Cancer Epidemiol Biomarkers Prev 22:675-80
Lindquist, Karla J; Jorgenson, Eric; Hoffmann, Thomas J et al. (2013) The impact of improved microarray coverage and larger sample sizes on future genome-wide association studies. Genet Epidemiol 37:383-92
Sakoda, Lori C; Jorgenson, Eric; Witte, John S (2013) Turning of COGS moves forward findings for hormonally mediated cancers. Nat Genet 45:345-8
Chang, Bao-Li; Spangler, Elaine; Gallagher, Stephen et al. (2011) Validation of genome-wide prostate cancer associations in men of African descent. Cancer Epidemiol Biomarkers Prev 20:23-32
Witte, John S (2010) Personalized prostate cancer screening: improving PSA tests with genomic information. Sci Transl Med 2:62ps55
Tai, Yu Chuan; Kvale, Mark N; Witte, John S (2010) Segmentation and estimation for SNP microarrays: a Bayesian multiple change-point approach. Biometrics 66:675-83

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