Characterizing Novel Aggressive Prostate Cancer Subtypes Associated with Loss of Chromosomes 8p and 16q
Abstract
In 2020, nearly 192,000 men will be diagnosed with prostate cancer and 33,000 men will die from the disease. If we had a better understanding of the genetic and biological causes of lethal prostate cancer, we could develop therapeutic interventions that could decrease cancer deaths. The Cancer Genome Atlas has defined eight groups of primary prostate cancer based on single molecular alterations. However, none of these groups has shown to be more or less lethal than the other. This further highlights the need to find and characterize subtypes of prostate cancer that decrease chances of survival. One prognostic indicator used in prostate cancer is Gleason score, which is a based on direct morphological observation of primary tumor biopsies. Patients with high Gleason scores have poorer prognoses. Genes, which reside on chromosomes, serve to instruct the cells in our body to perform specific functions. Some genes function to suppress cancer characteristics and are called tumor suppressors. When these genes are lost or mutated within the genome of a cell, there is an increased likelihood of that cell becoming cancerous. Chromosomal regions containing hundreds of genes on chromosome arms 8p and 16q are commonly lost in prostate cancer. Yet, a methodical study to identify the tumor suppressors in these regions and how their loss promotes prostate cancer has not been conducted. We found focal regions on 8p and 16q containing 48 genes and 58 genes, respectively, that showed strong links to either high Gleason scores or decreased survival in patients in The Cancer Genome Atlas cohort. Our preliminary data point to co-loss of BNIP3L (8p) and USP10 (16q) as characterizing a novel lethal subtype. There are likely other aggressive prostate cancer subtypes involving loss of our 8p and 16q candidate genes. The objective of this project is to fully define how co-loss of BNIP3L and USP10 cause lethal prostate cancer, identify therapeutic targets to treat this lethal subtype, prioritize genes on chromosomes 8p and 16q that suppress prostate cancer for further investigation, and provide training to assist me in reaching my career goal of being an independent investigator at the forefront of prostate cancer research. This project will directly contribute to three of the Prostate Cancer Research Program Overarching Challenges. The first aim of my project is to define the biology of the novel lethal prostate cancer involving co-loss of BNIP3L and USP10. Understanding how this subtype results in decreased disease-free survival will enable me to identify therapies that could almost immediately be started in clinical trials to treat men suffering from this subtype of prostate cancer. This too will be addressed in Aim 1 of my project. Finding specific and efficient treatments will subsequently improve the quality of life for survivors of prostate cancer by decreasing unnecessary and ineffective treatments that negatively affect quality of life. The second aim of my project, to prioritize additional genes on chromosomes 8p and 16q for further study, will provide insight in other molecular mechanisms of how co-loss of chromosome 8p and 16q causes lethal prostate cancer. This aim does not have as immediate clinical implications. However, Aim 2 will provide data to support future projects characterizing newly identified lethal prostate cancer subtypes and my career as an independent researcher. I aspire to be a prominent prostate cancer researcher. To achieve this goal, I need to conduct impactful research and acquire desirable technical, communication, collaborative, and leadership skills. This project and the training I will receive has been tailored to develop these skills. The proposed research has valuable clinical implications and will allow me to sharpen the technical skills I already possess and gain new prostate cancer-specific ones. Specifically, I will become more proficient using cell culture and mouse models, mo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110133
Entities
People
- Gabriel Yette
Organizations
- United States Army
- University of Colorado Denver