Discovery and Functional Analyses of Susceptibility Genes for Lethal Prostate Cancer
Abstract
While there continues to be much debate about PSA screening for prostate cancer leading to overdiagnosis and overtreatment of non-life-threatening disease, there continue to be nearly 30,000 men that die from prostate cancer each year, making it the second leading cause of cancer deaths in U.S. 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. In other patients at the time of diagnosis, it is very challenging to distinguish which men are more likely to develop an aggressive prostate cancer, as well as to determine the most effective treatment that offers the best clinical outcome. Multiple research studies provide strong evidence that a significant fraction (over half) of prostate cancers are inherited, or in other words, some prostate cancers are a result of specific, damaged genes passed down from father (or mother) to son, and this inherited form of prostate cancer is thought to be more common than inherited forms of breast or colon cancer. Recently, BRCA2, one the genes which when inherited in a damaged or mutated form causes breast and ovarian cancer, has been shown to be among the strongest genetic risk factors ever found for prostate cancer. Work from researchers worldwide has shown that men who inherit a damaged BRCA2 gene are 2 to 3 times more likely to be diagnosed with prostate cancer, and work from our laboratory and others has shown that the cancers diagnosed in men with BRCA2 mutations are much more likely to be capable of metastasizing and causing death. We estimate that about only about one in 15 to 20 men who die from prostate cancer carry a mutated BRCA2 gene. Our proposal seeks to find more genes like BRCA2, or stated differently, our hypothesis is that, out of the 20,000 different genes in the human genome, we think there are genes other than BRCA2 that are important in causing men to have a lethal prostate cancer. As part of our gene discovery program at Johns Hopkins, we have sequenced the inherited DNA from over 500 men with lethal prostate cancer, as well as ~1,000 men with prostate cancers highly likely to be harmless. We are in the midst of obtaining more sequence data, as we have an additional 4,500 cases that will be sequenced in the coming year. In this proposal, we will search and compare these existing and soon to be acquired data to find additional genes with characteristics of BRCA2, in particular, being mutated much more frequently in men with aggressive prostate cancers. We suspect that there are multiple other genes like BRCA2 that are yet to be discovered. Due to our unique patient resources, state-of-the art technology, and experience in this area (together with researchers at the University of Michigan, in 2012, we discovered HOXB13, the first susceptibility gene specific for prostate cancer), we feel we have an excellent chance to succeed in our search to find additional prostate cancer-causing genes. Surprisingly, one positive aspect of having a BRCA2 mutation is that it makes prostate cancer cells more sensitive to killing by certain drugs; that is, it makes the drugs work better. We will characterize the genes we find to see how they work to cause a more aggressive cancer and, in the process, seek out particular therapies that may work better in cancers caused by these new genes. Ultimately, the number of lives lost to prostate cancer can be drastically decreased with use of better genetic tests with more genes that predict which men are more likely to develop aggressive prostate cancer. Cancer-causing inherited changes can be detected with a simple, but accurate and inexpensive saliva DNA test. We estimate that the number of lives saved in the United States alone would approach 5,000 each year as optimized disease screening and treatment approaches take advantage of this new information. Even if we find only t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910345
Entities
People
- William B Isaacs
Organizations
- Johns Hopkins University
- United States Army