Germline Influence on Prostate Cancer Metastasis and Treatment Response
Abstract
Rationale: Prostate cancer is a genetic disease, but most men with prostate cancer do not have a single bad gene or mutation that runs in the family. Instead, prostate cancer risk is inherited as the combination of numerous genetic factors. We have developed genetic scores that predict very well who will get prostate cancer. Unfortunately, current genetic scores do not distinguish between men at risk of lethal prostate cancer and men at risk of harmless prostate cancer. We recently looked at normal DNA and tumor specimens from the same people. We found that genetic markers in a man’s normal DNA (i.e., what he inherited at birth) predicted what kind of prostate cancer he had. The DNA a man is born with influences not only whether he will get prostate cancer, but also what kinds of mutations caused his cancer to develop and what kind of molecular abnormalities his cancer has. Therefore, we could use genetic tests to predict whether he might have—or develop—lethal cancer. If he does have an aggressive prostate cancer, we could combine results from tests of his birth DNA with molecular tests of his tumor to help doctors make better treatment decisions. We are proposing in the present study to investigate these concepts using data from a large clinical trial that compared moderate or high doses of radiation therapy for men with prostate cancer. Objective: To determine whether inherited genetic features are predictive of clinically relevant tumor types and of risk of developing metastatic prostate cancer. Aims: First, we will evaluate whether inherited genetic factors described in our previous work are able to predict which men from the clinical trial eventually developed metastatic prostate cancer after their initial treatment with radiation therapy. We will also test whether we can predict which men benefit from higher radiation therapy doses. Second, we will study how well genetic markers predict the pattern of tumor DNA methylation, which is a tool cells use to turn on or off certain genes. Thus, we will learn about how inherited DNA influences cancer cell behavior. Third, we will consider the influence of ancestry and race. Black men are more likely to die from prostate cancer. While race is defined in social terms, we have found that African genetic ancestry likely contributes to the higher risk of prostate cancer death. We will investigate how genetic drivers of aggressive prostate cancer might differ for Black men. Finally, we will explore some additional concepts, including genetic risk of side effects from radiation therapy. What Are the Likely Contributions of this Study to the FY22 PCRP Overarching Challenges? We will develop genetic tests to predict who is at risk of progression to lethal prostate cancer. We will determine whether genetics can tell us which patients need a higher dose of radiation. We will explore whether genetic tests can help predict side effects of treatment so that they can be avoided, in an effort to improve quality of life. We will study genetic contributions to health disparities to help us eliminate the increased risk of prostate cancer death in Black men. What Types of Patients Will Be Helped and How Will It Help Them? We could identify men who have a high genetic risk of aggressive prostate cancer so that we can invite them to get screened and find the cancer before it has spread. Patients who already have prostate cancer will be helped, too. We will use genetic tests to predict who needs more intense treatment and what treatment dose is safest for them. We will learn about how genetics and race interact to contribute to prostate cancer risk. What are the potential clinical applications, benefits, and risks? The clinical applications are described in answer to the question above. There is no risk to any participants in this study because we are using specimens collected in a previous clinical trial. What is the Projected Time It May Take
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310532
Entities
People
- Tyler M Seibert
Organizations
- United States Army
- University of California, San Diego