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.

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, E. M.; Sboner, A.; Fedrizzi, T.; Mosquera, J. M.; Robinson, B. D.; De Sarkar, N.; Kunju, L. P.; Tomlins, S.; Wu, Y. M.; Rodrigues, D. N.; Loda, M.; Gopalan, A.; Reuter, V. E.; Pritchard, C. C.; Mateo, J.; Bianchini, D.; Miranda, S.; Carreira, S.; Rescigno, P.; Filipenko, J.; Vinson, J.; Montgomery, R. B.; Beltran, H.; Heath, E. I.; Scher, H. I.; Kantoff, P. W.; Taplin, M. -E.; Schultz, N.; Debono, J. S.; Demichelis, F.; Nelson, P. S.; Rubin, M. A.; Chinnaiyan, A. M.; Sawyers, C. L.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 116:23(2019), pp. 11428-11436. [10.1073/pnas.1902651116]

Genomic correlates of clinical outcome in advanced prostate cancer

Prandi D.;Benelli M.;Sboner A.;Fedrizzi T.;Demichelis F.;
2019-01-01

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.
2019
23
Abida, W.; Cyrta, J.; Heller, G.; Prandi, D.; Armenia, J.; Coleman, I.; Cieslik, M.; Benelli, M.; Robinson, D.; Van Allen, E. M.; Sboner, A.; Fedrizzi, T.; Mosquera, J. M.; Robinson, B. D.; De Sarkar, N.; Kunju, L. P.; Tomlins, S.; Wu, Y. M.; Rodrigues, D. N.; Loda, M.; Gopalan, A.; Reuter, V. E.; Pritchard, C. C.; Mateo, J.; Bianchini, D.; Miranda, S.; Carreira, S.; Rescigno, P.; Filipenko, J.; Vinson, J.; Montgomery, R. B.; Beltran, H.; Heath, E. I.; Scher, H. I.; Kantoff, P. W.; Taplin, M. -E.; Schultz, N.; Debono, J. S.; Demichelis, F.; Nelson, P. S.; Rubin, M. A.; Chinnaiyan, A. M.; Sawyers, C. L.
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, E. M.; Sboner, A.; Fedrizzi, T.; Mosquera, J. M.; Robinson, B. D.; De Sarkar, N.; Kunju, L. P.; Tomlins, S.; Wu, Y. M.; Rodrigues, D. N.; Loda, M.; Gopalan, A.; Reuter, V. E.; Pritchard, C. C.; Mateo, J.; Bianchini, D.; Miranda, S.; Carreira, S.; Rescigno, P.; Filipenko, J.; Vinson, J.; Montgomery, R. B.; Beltran, H.; Heath, E. I.; Scher, H. I.; Kantoff, P. W.; Taplin, M. -E.; Schultz, N.; Debono, J. S.; Demichelis, F.; Nelson, P. S.; Rubin, M. A.; Chinnaiyan, A. M.; Sawyers, C. L.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 116:23(2019), pp. 11428-11436. [10.1073/pnas.1902651116]
File in questo prodotto:
File Dimensione Formato  
11428.full.pdf

accesso aperto

Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Creative commons
Dimensione 1.23 MB
Formato Adobe PDF
1.23 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/240943
Citazioni
  • ???jsp.display-item.citation.pmc??? 480
  • Scopus 703
  • ???jsp.display-item.citation.isi??? 695
social impact