Significance of BRCA2 and RB1 co-loss in aggressive prostate cancer progression

Goutam Chakraborty, Joshua Armenia, Ying Z. Mazzu, Subhiksha Nandakumar, Konrad H. Stopsack, Mohammad O. Atiq, Kazumasa Komura, Lina Jehane, Rahim Hirani, Kalyani Chadalavada, Yuki Yoshikawa, Nabeela A. Khan, Yu Chen, Wassim Abida, Lorelei A. Mucci, Gwo Shu Mary Lee, Gouri J. Nanjangud, Philip W. Kantoff

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Purpose: Previous sequencing studies revealed that alterations of genes associated withDNAdamage 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.

Original languageEnglish
Pages (from-to)2047-2064
Number of pages18
JournalClinical Cancer Research
Issue number8
StatePublished - 15 Apr 2020
Externally publishedYes


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