Rare Variants in 8q24 in African Population Are Associated with Prostate Cancer Progression
Abstract
My career goals are to continue my scientific development to permit me to become an independent investigator, focused on prostate cancer research, and to establish my own prostate cancer research program. I will take advantage of the remarkable insights provided by deep genetic sequence-based information now available to uncover new, attackable aspects of prostate cancer etiology and discover novel therapeutic targets. For this reason, I selected a project that can significantly improve the quality of life of prostate cancer patients and prolong their overall survival rate, especially for those with castrate-resistant prostate cancer (CRPC). I elected to do postgraduate training in Dr. Rosenfeld s laboratory and to also benefit from his long-standing collaboration with Professor Christopher Haiman at the USC Keck School of Medicine. Indeed, this training, which combines contemporary genetics and global genomics, will effectively prepare me for both basic and translational approaches to prostate cancer. My training will also take advantage of the frequent collaborative meetings with scientists at other local institutions including the Biology Department, the UCSD Moores Cancer Center, the Salk Institute, the Sanford/Burnham/Prebys Institute, and The Scripps Research Institute (TSRI). This extensive educational network provides strong support to solve central questions in prostate cancer that I hope will directly provide rapid clinical benefits. My ultimate goal under this grant proposal is to identify the molecular basis for a genetic predisposition to prostate cancer in the African American population. Now, based on consortia that identify prostate cancer-related disease susceptibility loci, I can propose the prognostic significance of SNPs in the 8q24 locus, one of the most prevalent genetic links to prostate cancer in African American men. Here, I will extend these genetic finding by investigating the specific sequence variants that link to risk of prostate cancer, and focus on regulatory variants that reside in regions that do not harbor the classic marks of enhancers, implying a new type of regulatory element that links to gene transcriptional programs and cancer. To study this, I propose to investigate the potential regulatory role of this disease risk locus to the function of promoters for several long non-coding RNAs in the 8q24 region that are associated with diagnosis and survival of prostate cancer patients. Using global strategies to detect looping interactions between chromosomal regions and functional studies employing a technique referred to as global run-off transcription sequence (GRO-seq), I hope to be able to uncover the molecular basis of this new type of cancer-associated regulatory sequence. Based on my preliminary data, I will explore the hypothesis that the DNA binding transcription factor c-MYB normally binds to this regulatory sequence, inhibiting transcription of cancer-related transcription units; the risk allele is suggested to lose this binding and cause increased transcription of cancer-inducing genes. I will determine these causal genes and use different strategies to prove the critical functions of c-MYB in these events. These research objectives can be completed in the 2-year period of this fellowship, and my Mentor has indicated his enthusiastic support of these research objectives. The findings under this proposal will provide insights into prostate cancer risk in African American men identify a new class of regulatory element and uncover roles of c-MYB in prostate cancer. Although >32,000 men die in the United States annually of metastatic disease, African Americans are particularly susceptible to developing prostate cancer. Although there are multiple genetic aspects to this, the 8q24 locus is one of the best-established risk regions, and here I can both identify and mechanistically understand the basis for this prostate cancer risk. In achieving this, I will not only
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610548
Entities
People
- Fan Yang
Organizations
- United States Army
- University of California, San Diego