Significant Evidence For Linkage For Lethal Prostate Cancer On Chromosome Arm 4q In Utah High-Risk Pedigrees

Background: Using the unique Utah genealogical resource that links 12 generations of genealogy data to a statewide cancer registry from 1966 and statewide death certificates from 1904 we have identified a set of high-risk lethal prostate cancer pedigrees with a significant excess of prostate cancer cases having died from prostate cancer. Methods: Clusters of prostate cancer cases descended from a common ancestor, among whose descendants is observed a statistical excess of prostate cancer (high-risk prostate cancer pedigrees) were recruited and sampled over the past 25 years. Pedigrees including 4 or more cases who have subsequently been reported to have died from prostate cancer (as evidenced by inclusion as a cause of death on a Utah death certificate) were genotyped with 720k high-density SNPs across the genome. Linkage analysis with markers not in linkage disequilibrium was performed to identify regions hypothesized to contain a lethal prostate cancer predisposition gene. Results: A single extended Utah high-risk prostate cancer pedigree (p Conclusions: The inability of association studies to identify prostate cancer predisposition genes has returned focus to linkage studies of highly informative high-risk pedigrees, which provide power for identifying and localizing regions of interest for predisposition genes. A focus on only those prostate cancer cases who are members of high-risk lethal prostate cancer pedigrees, who also went on to die as a result of their prostate cancer, has resulted in the identification of evidence for a prostate cancer predisposition gene on chromosome arm 4q24, confirming a previous GWAS that reported association with prostate-cancer-specific-survival (Pomerantz MM et al., 2011) in this region harboring TET2 (a tumor suppressor gene involved in pathogenesis of acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms), and PP2A (implicated in androgen receptor regulation in prostate cancer cell lines). Citation Format: Lisa A. Cannon-Albright, craig C. TEERLINK, Robert A. Stephenson, Neeraj Agarwal. Significant evidence for linkage for lethal prostate cancer on chromosome arm 4q in Utah high-risk pedigrees. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2746. doi:10.1158/1538-7445.AM2015-2746