Integrative Dissection of Germline Genomic Features Driving Cancer Risk, Disease Progression, and Response to Therapy in Prostate Cancer
Abstract
Integrative Dissection of Germline Genomic Features Driving Cancer Risk, Disease Progression, and Response to Therapy in Prostate Cancer Significance and Background: The analysis of the inherited genetic changes (also called germline variants) has been increasingly used to guide the clinical care of cancer patients. In prostate cancer, genetic analysis can identify carriers of damaging germline variants (called pathogenic) that are associated with a substantially increased risk of prostate cancer who can benefit from a more personalized clinical management plan where screening and other risk-reducing measures can be implemented. In addition to being informative for prostate cancer risk, pathogenic variants in certain genes (such as BRCA2) are associated with a higher risk of disease progression and failure of therapy. Furthermore, prostate cancer patients who carry certain pathogenic germline variants tend to have a better response to specific therapeutic interventions. However, despite the established utility of germline genetic information in managing prostate cancer patients, this approach is severely limited by the lack of a complete understanding of which germline variants are clinically and biologically important. General Study Approach: This study will aggregate and utilize the genetic data of prostate cancer patients (approximately 4,000 in total) who were sequenced in prior studies. Importantly, the germline genetic data of over 2,000 prostate cancer patients of African American ancestry will be an analyzed in this proposal. Expected Outcomes and Clinical Applicability: This proposal aims to achieve several clinically focused outcomes. First, the study aims to expand on what is known about the genetic mediators of prostate cancer risk and identify one or more new genes where pathogenic variants are also associated with a higher risk of prostate cancer. These new findings may explain why some families tend to have a very high risk of developing prostate cancer, yet they do not have any identifiable pathogenic variants to explain this inherited tendency. In addition, identifying new genes contributing to prostate cancer susceptibility can also highlight new mechanisms of prostate cancer initiation, which can be further investigated in future studies. Second, this study aims to explore the germline genetic makeup of patients with primary disease vs. those with metastatic disease to understand why only a subset of prostate cancer patients progress to advanced disease while, in others, the tumors never spread. Our past work has made contributions to the identification of BRCA2 as the first germline genetic change associated with an increased risk of prostate cancer progression and metastasis, which has informed the management recommendations for universal germline testing in advanced prostate cancer. In this study, we are building on these discoveries and systematically interrogate 20,000 genes to uncover additional germline markers of disease progression that can have a similarly immediate impact on prostate cancer management. Third, this proposal aims to jointly analyze the germline and tumor genetic changes in responders to therapy vs. non-responders to reveal new germline mediators of greater response to therapy. Such molecular markers can inform prostate cancer patients and their treating physicians when deciding on which treatment plan is likely to be most effective. Overall, the expected outcomes of this proposal will have an immediate impact on the management of prostate cancer patients and can be readily translated into clinical care. Contributions to the FY20 PCRP Overarching Challenges: The expected impact of this proposal is not limited to prostate cancer patients of European ancestry, as approximately 50% of the patients who will be analyzed in this proposal are of African American ancestry, while another 5-10% are prostate cancer patients from other understudied ethnic groups.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110084
Entities
People
- Saud H Aldubayan
Organizations
- Dana–Farber Cancer Institute
- United States Army