While family history is an important risk factor for prostate cancer, localization of highly penetrant prostate cancer susceptibility genes using traditional linkage analysis has been challenging. In this SPORE project, we used our ongoing study of hereditary prostate cancer study (the University of Michigan Prostate Cancer Genetics Project or PCGP) to identify a set of sibling pairs discordant for prostate cancer. These siblings can be used to implicate genes of modest penetrance using family-based association methods. Since the sibships are derived from families with early-onset and/or hereditary prostate cancer, they are relatively enriched for genetic susceptibility factors. During the first five years of funding, we have established the discordant sibling pair (DSP) project as a resource for characterizing germline variants associated with prostate cancer. To date, we have studied 14 candidate genes and have shown that single nucleotide DOlymorphisms (SNPs) in CYP17, BRCA1, FHIT, SDF1, CXCR4, and AMACRare significantly associated with prostate cancer. Our most compelling association finding involves a glutamine-to-arginine substitution at codon 356 (Gln356Arg) in exon 11 of the BRCA1 gene that accounts for some (but not all) of our prior vidence of prostate cancer linkage to chromosome 17q21 in a PCGP genome-wide linkage scan. Nonsynonymous SNPs (nsSNPs), such as BRCA1 Gln356Arg, result in single amino acid substitutions and have been shown to account for many of the genetic changes that influence Mendelian disorders. In this SPORE renewal project, we propose a genome-wide approach focusing on nsSNPs in known genes, including many genes previously implicated in cancer. This proposed genome-wide approach has the advantage of testing for variants that are likely to be causative and has been successfully used to identify novel candidate loci for type 1 diabetes and Crohn disease. To test the hypothesis that common nsSNPs in BRCA1 and other candidate genes are associated with prostate cancer, the following two Specific Aims are proposed:
Specific Aim 1 : Develop our new, formal collaboration with the SPORE program at Johns Hopkins University to follow-up and generalize significant prostate cancer associations, including our previously reported prostate cancer association with BRCA1 Gln356Arg.
Specific Aim 2. Complete a replication-based genome-wide association study of early-onset and familial prostate cancer using more than 11,500 nsSNPs that cover approximately 6,500 known human genes, including a disproportionate number in cancer-related pathways.
|Udager, Aaron M; Shi, Yang; Tomlins, Scott A et al. (2014) Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer. Prostate 74:1199-208|
|Johnson, Anna M; Zuhlke, Kimberly A; Plotts, Chris et al. (2014) Mutational landscape of candidate genes in familial prostate cancer. Prostate 74:1371-8|
|Prensner, John R; Chen, Wei; Iyer, Matthew K et al. (2014) PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res 74:1651-60|
|Asangani, Irfan A; Dommeti, Vijaya L; Wang, Xiaoju et al. (2014) Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510:278-82|
|Wang, Shaomeng; Sun, Wei; Zhao, Yujun et al. (2014) SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res 74:5855-65|
|Beebe-Dimmer, Jennifer L; Isaacs, William B; Zuhlke, Kimberly A et al. (2014) Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy. BJU Int 113:830-5|
|Yu, Zeta Tak For; Aw Yong, Koh Meng; Fu, Jianping (2014) Microfluidic blood cell sorting: now and beyond. Small 10:1687-703|
|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|
|Sarma, Aruna V; St Sauver, Jennifer L; Jacobson, Debra J et al. (2014) Racial differences in longitudinal changes in serum prostate-specific antigen levels: the Olmsted County Study and the Flint Men's Health Study. Urology 83:88-93|
|Davis, Elizabeth J; Beebe-Dimmer, Jennifer L; Yee, Cecilia L et al. (2014) Risk of second primary tumors in men diagnosed with prostate cancer: a population-based cohort study. Cancer 120:2735-41|
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