Long-Read DNA-Sequencing and Targeted RNA-Seq to Identify Previously Undetectable Classes of Mutations in Families with Lethal Prostate Cancer
Abstract
Recent research has revealed that about 10% of men with metastatic prostate cancer have their disease as the result of a mutation in a DNA repair gene. The culprit genes are the same as those that harbor mutations leading to breast and ovarian cancer in women. For men with metastatic prostate cancer and these mutations, the information is critical for screening, surveillance, diagnosis, and treatment. In particular, there are now chemotherapy drugs, recently approved by the FDA, that can benefit specifically patients with one of these mutations. As the result of this new information, testing for inherited mutations in DNA repair genes is now recommended for all men diagnosed with metastatic prostate cancer. The approach for identifying inherited mutations in DNA repair genes was developed in 2010 and has not changed much since then. It is very accurate for pinpointing most types of mutations. However, our research suggests that some types of mutations are missed by the 2010 approach. We can identify these previously missed mutations with new genomics technology. We undertook this work because we have encountered many families in which a patient and his father, brothers, and uncles have all developed prostate cancer, but no mutation was detected with conventional technology. Our PCRP proposal aims to identify classes of mutations that were previously undetectable in these patients and families. We directly address the Overarching Challenge of reducing lethal prostate cancer in a high-risk population; namely, men who are genetically predisposed to the disease, but without an identified causative mutation on which to take action. Specifically, we will search for cryptic and complex mutations that are hidden from current technologies in “messy” regions of the genome, but that nonetheless lead to loss of function of critical genes. Such messy genomic regions comprise large swaths of tumor suppressor genes that we know well, especially BRCA1, BRCA2, PALB2, and ATM. Our approach could benefit all men and their families who unknowingly carry inherited mutations predisposing to prostate cancer. The immediate impact of our study will be that participants will learn the cause of their prostate cancer, so that as-yet-unaffected young men and their relatives can be tested. Our laboratory is CLIA-certified for this purpose. Participants will be counseled by our genetic counselor Jessica Mandell, CGC, and clinical management will be undertaken by our colleague and co-investigator, Heather Cheng, M.D., Ph.D., medical oncologist and Director of the Prostate Cancer Genetics Clinic at the Seattle Cancer Care Alliance. We intend that this project will lead to improvements in genetic testing for inherited predisposition to prostate cancer for men throughout the U.S.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110343
Entities
People
- Tom Walsh
Organizations
- United States Army
- University of Washington