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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. 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. 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. 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. ©2019 American Association for Cancer Research.

Citation

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. Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Apr 15;26(8):2047-2064

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PMID: 31796516

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