Faculty Collaboration Database

Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A 2019 Jun 04;116(23):11428-11436

Date

05/08/2019

Pubmed ID

31061129

Pubmed Central ID

PMC6561293

DOI

10.1073/pnas.1902651116

Scopus ID

2-s2.0-85066600927 (requires institutional sign-in at Scopus site)   718 Citations

Abstract

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.

Author List

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

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Androstenes
Benzamides
Biomarkers, Tumor
Drug Resistance, Neoplasm
Genomics
Humans
Male
Middle Aged
Nitriles
Phenylthiohydantoin
Prostatic Neoplasms, Castration-Resistant
Receptors, Androgen
Treatment Outcome