PURPOSE: Previous sequencing studies revealed that alterations of genes 
associated with DNA damage response (DDR) are enriched in men with metastatic 
castration-resistant prostate cancer (mCRPC). BRCA2, a DDR and cancer 
susceptibility gene, is frequently deleted (homozygous and heterozygous) in men 
with aggressive prostate cancer. Here we show that patients with prostate cancer 
who have lost a copy of BRCA2 frequently lose a copy of tumor suppressor gene 
RB1; importantly, for the first time, we demonstrate that co-loss of both genes 
in early prostate cancer is sufficient to induce a distinct biology that is 
likely associated with worse prognosis.
EXPERIMENTAL DESIGN: We prospectively investigated underlying molecular 
mechanisms and genomic consequences of co-loss of BRCA2 and RB1 in prostate 
cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes 
in prostate cancer cell lines and subjected them to in vitro studies and 
transcriptomic analyses. We developed a 3-color FISH assay to detect genomic 
deletions of BRCA2 and RB1 in prostate cancer cells and patient-derived mCRPC 
organoids.
RESULTS: In human prostate cancer cell lines (LNCaP and LAPC4), loss of BRCA2 
leads to the castration-resistant phenotype. Co-loss of BRCA2-RB1 in human 
prostate cancer cells induces an epithelial-to-mesenchymal transition, which is 
associated with invasiveness and a more aggressive disease phenotype. 
Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived 
organoids and human CRPC cells harboring single-copy loss of both genes.
CONCLUSIONS: Our findings suggest that early identification of this aggressive 
form of prostate cancer offers potential for improved outcomes with early 
introduction of PARP inhibitor-based therapy.See related commentary by Mandigo 
and Knudsen, p. 1784.