Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression

• Published in: Clinical cancer research Vol. 26; no. 8; pp. 2047 - 2064
• Main Authors: Chakraborty, Goutam, Armenia, Joshua, Mazzu, Ying Z., Nandakumar, Subhiksha, Stopsack, Konrad H., Atiq, Mohammad O., Komura, Kazumasa, Jehane, Lina, Hirani, Rahim, Chadalavada, Kalyani, Yoshikawa, Yuki, Khan, Nabeela A., Chen, Yu, Abida, Wassim, Mucci, Lorelei A., Lee, Gwo-Shu Mary, Nanjangud, Gouri J., Kantoff, Philip W.
• Format: Journal Article
• Language: English
• Published: United States 15.04.2020
• Subjects: Biomarkers, Tumor; BRCA2 Protein; Genes, BRCA2; Humans; Male; Phenotype; Prostatic Neoplasms, Castration-Resistant - genetics
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1570

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). , 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 frequently lose a copy of tumor suppressor gene ; 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 and 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 studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of and in prostate cancer cells and patient-derived mCRPC organoids. In human prostate cancer cell lines (LNCaP and LAPC4), loss of leads to the castration-resistant phenotype. Co-loss of - 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. .