The Role of Mutations in BRCA2 and Other Known and Novel Cancer Susceptibility Genes in Inherited Risk for Lethal Prostate Cancer
Abstract
While there continues to be much debate about prostate-specific antigen (PSA) screening for prostate cancer leading to overdiagnosis and overtreatment and of non-life-threatening disease, there continues to be nearly 30,000 men that die from prostate cancer each year, making it the second leading cause of cancer deaths in US men. Many of these men have prostate cancer that has spread throughout the body at the time of their diagnosis -- these men are diagnosed too late as the vast majority of them will die from their disease. At the time of diagnosis, it is challenging to distinguish which men are more likely to develop an aggressive prostate cancer as well as the most effective treatment that will lead to better patient outcomes. Our proposal is motivated by two exciting new studies completed over the last several months. One is our own preliminary study of 96 patients who died of prostate cancer before age 65 years, a very unique group of prostate cancer patients. We found that as many as one of every three of these patients has an inherited defect (mutation) in DNA repair genes. These mutations hinder our bodies ability to correct errors in DNA. These results are significant in that they suggest, for the first time, that many lethal/aggressive prostate cancers may be a special form of prostate cancer that is associated with and likely even caused by inherited mutations. Knowledge of these mutations will help determine which men are more likely to develop lethal/aggressive prostate cancer. It can also help clinicians distinguish which patients will have life-threatening disease at the time of diagnosis to guide treatment decisions. Furthermore, because there are specific drugs that work much on cancers with defects in DNA repair genes, knowing that a patient harbors a mutation in a DNA repair gene provides clinicians further information for selecting the most effective treatment strategy. In this study, we are proposing the most comprehensive study to date of inherited mutations in prostate cancer patients with advanced disease, in which we will look at all genes in the genome among large numbers of patients who died of prostate cancer at an early age (before 75 years of age). The first major objective of this project is to determine how many men who die from prostate cancer have inherited an important but defective DNA repair gene or other cancer-associated gene. The second major objective is to establish a causal relationship between these inherited mutations and lethal prostate cancer using various state-of-the-art methods. The final major objective is to develop and validate a tool (a genetic test) that predicts which men are likely to develop lethal/aggressive prostate cancer and to distinguish which patients will have life-threatening disease at the time of diagnosis. Because of the scale and complexity of the proposed project, we assembled a strong team of investigators that engages three Partnering Principal Investigators (PIs). These PIs are a leading prostate cancer biologist, along with a leading oncological clinician, and a leading cancer genomicist who have been collaborating for over 20 years. With our combined experience and available patient resources totaling over 10,000 prostate cancer patients of various ancestries, including samples from ~700 patients who died of prostate cancer, we feel we have the best chance possible to achieve our major objectives. Ultimately, the number of lives lost to prostate cancer could significantly decrease with use of genetic tests that predict which men are more likely to develop aggressive prostate cancer and more efficient drug treatments targeting specific weaknesses in a given patient s cancer cells. We estimate that the number of lives saved in the United States alone could approach 5,000 each year as optimized disease screening and treatment paradigms that leverage these concepts are established.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610765
Entities
People
- Jianfeng Xu
Organizations
- NorthShore University HealthSystem
- United States Army