Long-Read DNA-Sequencing and Targeted RNA-Seq to Identify Previously Undetectable Classes of Mutations in Families with Lethal Prostate Cancer
Abstract
Prostate cancer has a significant heritable component, with 10-15% of patients with advanced disease harboring pathogenic germline mutations in DNA repair genes. It is critical for these patients to know their genotypes, because mutations in BRCA2and PALB2, and to a more modest degree BRCA1 and ATM, predict favorable response to poly-ADP ribose polymerase inhibitors (PARPi) and platinum chemotherapy. In May 2020, the FDA approved two PARPi drugs for men with metastatic castration resistant prostate cancer and mutations in these genes. However, many patients with metastatic prostate cancer and severe family histories remain without a detected germline pathogenic mutation. These patients cannot benefit from molecularly-directed therapies, because these drugs are useful only to patients with damaging mutations in DNA repair genes,and hence are targeted only to them. Our proposal aims to identify previously undetectable classes of pathogenic mutations in450 patients for whom no pathogenic mutation has been found by gene-panel sequencing. We will use two newly developed genomic techniques: 1) CRISPR excision and long-read sequencing to identify complex structural mutations and 2) targeted RNA-Seq to evaluate patient RNA for cryptic regulatory and splice variants.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2022
- Accession Number
- AD1190563
Entities
People
- Tom Walsh
Organizations
- University of Washington