Investigating Long Noncoding RNAs as Biomarkers and Mediators of Prostate Cancer Progression in African American Men
Abstract
It is evident that there are racial differences in both prostate cancer incidence and mortality. Epidemiological studies demonstrate that African American (AA) men suffer from the highest rates of prostate cancer in the world, and consistently experience greater mortality from this disease compared to white/Caucasian (CA) men. While it is probable that prostate cancer in AA men is mediated by different biological drivers than prostate cancer in CA men, all the large genomic sequencing studies published to date have investigated prostate cancer in cohorts comprised primarily of CA patients. We recently performed a meta-analysis assessing the racial distribution of samples sequenced within The Cancer Genome Atlas (TCGA) and found that TCGA data significantly under-represent racial minorities. In total, these findings suggest that dedicated efforts, particularly in the context of genomics studies, are needed to avoid widening the already pervasive gap in healthcare disparities. To address this gap, we propose to comprehensively investigate the role of a relatively unexplored area of the cancer genome -- long noncoding RNAs (lncRNAs) -- in prostate cancer progression in AA men. LncRNAs arise from genes that make RNA that are not made into proteins, thus differing from the conventional protein-coding genes on which the vast majority of cancer research has focused to date. In a study analyzing gene expression in prostate cancer samples from over 1000 predominantly CA patients, we found that the expression of certain lncRNAs more strongly predicted disease recurrence than the traditionally studied protein-coding genes. Moreover, we have recently performed a large bio-informatics-based analysis of sequencing data and have identified 48,952 new, previously uncharacterized, lncRNAs in the cancer genome. Thus, it is clear that lncRNAs represent a very promising frontier of genetics -- one that is untapped but has tremendous potential. In this application, we now propose three specific aims designed to determine the clinical and functional significance of lncRNAs associated with poor prognosis in AA men with prostate cancer. In Aim 1, we will analyze the expression of lncRNAs in 410 prostate cancer samples from AA men to determine which of these genes are most strongly associated with disease recurrence. In Aim 2, we will perform a similar analysis, but in the context of 200 urine samples from AA patients with prostate cancer, to identify lncRNAs that can serve as non-invasive biomarkers (that could help determine aggressive disease in the absence of a biopsy). In Aim 3, we have generated a unique laboratory model of prostate cancer called organoids -- these are prostate cancer cells, obtained from clinical samples, that recapitulate the architecture of the prostate gland and prostate cancer when grown in laboratory dishes. We have generated organoids from AA patients and will use these unique models to study the underlying biological changes mediated by lncRNAs in prostate cancers from AA men. To our knowledge, our proposal is the first to comprehensively study the biology underlying prostate cancers from AA men, using tumor samples, urine samples, and organoid models. In addition, our application is the first, to our knowledge, to investigate lncRNAs as prognostic biomarkers or disease drivers of prostate cancer in AA patients. We believe that our study will provide a wealth of information regarding potential new biomarkers or therapeutic targets to investigate in AA men. Ultimately, our hope is that novel lncRNA biomarkers will allow physicians to select therapies based on the genetic makeup of an individual s tumor and allow for truly personalized care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710302
Entities
People
- Felix Y. Feng
Organizations
- United States Army
- University of California, San Francisco