The Role of Genomic Diversity in Clinically High-Risk Prostate Cancer
Abstract
Prostate Cancer. Prostate cancer is the most common non-skin cancer in men in the United States. It afflicts over 10% of men during the course of their lives. While many prostate cancers are non-lethal, others are extremely aggressive and kill men rapidly. While prostate cancers can stay localized to the prostate, many high-risk localized prostate cancers can spread or metastasize to other issues within the body. This metastatic spread of prostate cancers to other tissues can be hard to catch on initial diagnosis, which therefore affects clinical management and treatment. Interestingly, the genetics that lead to metastatic spread of high-risk prostate cancer are not well known. Therefore, understanding this process would potentially pave the way for improving cure of high-risk localized disease. Prostate Cancer Genomics. Cancer at its root is a disease of the genome. Some of the three billion letters of DNA present in each cell will mutate, with one letter replacing another. These mutations can lead some cells to grow faster or to be less capable of fixing mutations as they occur and leads to genomic diversity in each cancer. As a result, cancers slowly emerge over time. So, DNA mutations really underlie prostate cancer, and all cancers. However, this DNA information has not generally been helpful for prostate cancer patients. There are a few exceptions, like the wide-spread testing for BRCA2 mutations. But while DNA sequencing has transformed many other types of cancer, it has had less impact on prostate cancer. Objective. We hypothesize that tumors that evolve faster are more likely to metastasize and kill patients. We can have created algorithms to estimate the speed of evolution by looking at the patterns of mutations in a tumor. We will focus on patients with high-risk localized tumors – those at the highest risk of metastasis. First, we will use DNA sequencing and our algorithms to quantify whether evolutionary speed predicts for metastasis. Second, we will combine our new data with preexisting databases of prostate cancer DNA sequencing to try to understand why some tumors are evolving faster than others, and if specific cancer genes like BRCA2 might explain this. What do we hope to find? In the short term, this work will aim to assess if genomic diversity is a robust biomarker for metastatic spread of high-risk localized prostate cancer. If tumors that present with high genomic diversity also present with an elevated risk of spread or metastasis or the opposite (low genomic diversity and low metastatic spread), then potentially this work could be translated to inform treatment plans. In the long term, from a basic science perspective, these studies aim to better understand the biology behind how and why lethal prostate cancers evolve, which would add to the broader scientific community. Applicability. This work has the potential to help all prostate cancer patients by leveraging patient samples with pre-existing clinical data and genomic databases. Each of the existing DNA sequencing datasets has come from the investment of millions of dollars and donated patient samples. First, we will use DNA sequencing and computational algorithms to understand why some tumors evolve faster than others. This is a medium-term activity and can be expanded upon as new datasets and patient samples become available. Additionally, understanding how the genetics of prostate tumors evolve or change during disease can aid in our biological understanding of how these tumors escape treatment. Identifying biomarkers for metastatic spread of high-risk localized disease can help inform treatment options. The immediate impact of our study would be a large dataset of clinically well-annotated, high-risk, localized tumors with deep whole-genome sequencing of tumor and normal and associations with long-term clinical information. This would fill a key gap in our characterization of the genomics of prostate ca
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210751
Entities
People
- Paul C. Boutros
Organizations
- United States Army
- University of California, Los Angeles