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

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

Authors:	Chakraborty, G.; Armenia, J.; Mazzu, Y. Z.; Nandakumar, S.; Stopsack, K. H.; Atiq, M. O.; Komura, K.; Jehane, L.; Hirani, R.; Chadalavada, K.; Yoshikawa, Y.; Khan, N. A.; Chen, Y.; Abida, W.; Mucci, L. A.; Lee, G. S. M.; Nanjangud, G. J.; Kantoff, P. W.
Article Title:	Significance of BRCA2 and RB1 co-loss in aggressive prostate cancer progression
Abstract:	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.
Keywords:	breast; dna; heterozygosity; androgen receptor; ovarian-cancer; synthetic lethality; mutational landscape; distinct; regions; mammary-tumors; allelic loss
Journal Title:	Clinical Cancer Research
Volume:	26
Issue:	8
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2020-04-15
Start Page:	2047
End Page:	2064
Language:	English
ACCESSION:	WOS:000526058100029
DOI:	10.1158/1078-0432.Ccr-19-1570
PROVIDER:	wos
PUBMED:	31796516
PMCID:	PMC7416644
Notes:	Article -- Source: Wos