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Proc Natl Acad Sci U S A January 1, 2019; 116 (23): 11428-11436.

Genomic correlates of clinical outcome in advanced prostate cancer.

Abida W , Cyrta J , Heller G , Prandi D , Armenia J , Coleman I , Cieslik M , Benelli M , Robinson D , Van Allen EM , Sboner A , Fedrizzi T , Mosquera JM , Robinson BD , De Sarkar N , Kunju LP , Tomlins S , Wu YM , Nava Rodrigues D , Loda M , Gopalan A , Reuter VE , Pritchard CC , Mateo J , Bianchini D , Miranda S , Carreira S , Rescigno P , Filipenko J , Vinson J , Montgomery RB , Beltran H , Heath EI , Scher HI , Kantoff PW , Taplin ME , Schultz N , deBono JS , Demichelis F , Nelson PS , Rubin MA , Chinnaiyan AM , Sawyers CL .

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

PubMed ID: 31061129
PMC ID: PMC6561293
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Echinodermata
Genes referenced: LOC105441887 LOC115923239 LOC588766 rb1

Article Images: [+] show captions
References [+] :
Abida W, Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. 2017, Pubmed