Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with distinct homologous recombination deficiency associated DNA aberration profiles

BackgroundAfrican American (AA) men have significantly higher mortality rates from prostate cancer (PC) than individuals of European ancestry (EA). Therapeutically targetable molecular differences may hold the potential to reduce this disparity.ObjectiveTo investigate chromodomain helicase DNA-binding protein 1 (CHD1) deletion both as a cause of aggressive disease and therapeutic vulnerability in the prostate cancer of AA men.Design, setting, and participants91 AA and 109 EA prostate cancer cases were analyzed by fluorescence in situ hybridization (FISH) for the deletion of CHD1. Whole exome and whole genome sequencing data from prostate adenocarcinoma cases were analyzed for mutational signatures from AA and EA individuals.Outcome measurements and statistical analysisAssociations with biochemical recurrence were evaluated using Cox proportional hazard regression models. Association between mutational signatures and CHD1 deletion were assessed by Wilcoxon ranked sum tests.Results and limitationsSubclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of men than in EA men. CHD1 deletion is associated with some of the homologous recombination deficiency associated mutational signatures in prostate cancer. In a cell line model CHD1 deletion induced 1-10 kb deletions resembling those induced by BRCA2 deficiency. CHD1 deficient cells showed markedly increased sensitivity to both talazoparib and the radiomimetic bleomycin.ConclusionsCHD1 is more frequently deleted in the prostate cancer of AA men. This deletion is both associated with and induces mutational signatures characteristic of BRCA2 deficiency. CHD1 deficient prostate cancer is more sensitive to talazoparib or bleomycin treatment.Patient summarySubclonal deletion of CHD1 is more frequent in the prostate cancer of AA men and this could be one of the reasons behind more aggressive disease. CHD1 deletion, however, also constitutes a therapeutic vulnerability to the PARP inhibitor talazoparib. This treatment may significantly improve the outcome of disease in AA men.