Defining Mutations of DNA Repair Genes in Prostate Cancer Patients Towards Enhancing Treatment
Technical Report,01 May 2018,30 Apr 2019
Henry M. Jackson Foundation Bethesda United States
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DNA damage repair genes DDRGs are critical for protecting genome integrity and have been implicated in several cancer types. Recent genomic studies of metastatic castration resistant prostate cancer mCRPC highlight the contributions from mutations or copy number changes in DDRG alterations, including BRCA1, BRCA1, ATM, CHEK2, and MSH2. It has also been shown that prostate cancer CaP patients harboring inherited mutations in DDRGs may benefit from early targeted PARP inhibitor therapy. However, the association of germline mutations of DDRGs with earlier stage high risk CaP patients remains to be defined. Accumulating evidence suggest for increased association of BRCA2 mutations with more aggressive CaP. Our recent data show an association of increased frequency of BRCA2 gene mutations in CaP patients with African ancestry with elevated risk of developing metastasis. We hypothesize that AA CaP patients have an increased frequency of mutated DDRGs. We aim to assess blood derived germline DNAs of AA N300 and CA N300 CaP patients archived in USU-CPDR, Center of Excellence, for the association frequency all known DDRGs genomic alterations with disease aggressiveness based on pathologic grade, pathologic stage, time to recurrence metastasis, family history and African ancestry. The results will be assessed to refine patient stratification for specific targeted therapy. Longer term implication of this project will impact early targeted therapy to reduce of racial disparity in CaP, given a higher anticipated rate of DDRG mutations in AA CaP patients. Within the DOD context, outcome of this research strategy will be valuable for developing approaches to reduce mutagenic exposures of affected service members and have a broader impact on other inherited cancers.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research