Integrative clinical genomics of advanced prostate cancer.

Abstract

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

• Authors: Dan Robinson, Eliezer M Van Allen, Yi-Mi Wu, Nikolaus Schultz, Robert J Lonigro, Juan-Miguel Mosquera, Bruce Montgomery, Mary-Ellen Taplin, Colin C Pritchard, Gerhardt Attard, Himisha Beltran, Wassim Abida, Robert K Bradley, Jake Vinson, Xuhong Cao, Pankaj Vats, Lakshmi P Kunju, Maha Hussain, Felix Y Feng, Scott A Tomlins, Kathleen A Cooney, David C Smith, Christine Brennan, Javed Siddiqui, Rohit Mehra, Yu Chen, Dana E Rathkopf, Michael J Morris, Stephen B Solomon, Jeremy C Durack, Victor E Reuter, Anuradha Gopalan, Jianjiong Gao, Massimo Loda, Rosina T Lis, Michaela Bowden, Stephen P Balk, Glenn Gaviola, Carrie Sougnez, Manaswi Gupta, Evan Y Yu, Elahe A Mostaghel, Heather H Cheng, Hyojeong Mulcahy, Lawrence D True, Stephen R Plymate, Heidi Dvinge, Roberta Ferraldeschi, Penny Flohr, Susana Miranda, Zafeiris Zafeiriou, Nina Tunariu, Joaquin Mateo, Raquel Perez-Lopez, Francesca Demichelis, Brian D Robinson, Marc Schiffman, David M Nanus, Scott T Tagawa, Alexandros Sigaras, Kenneth W Eng, Olivier Elemento, Andrea Sboner, Elisabeth I Heath, Howard I Scher, Kenneth J Pienta, Philip Kantoff, Johann S de Bono, Mark A Rubin, Peter S Nelson, Levi A Garraway, Charles L Sawyers, Arul M Chinnaiyan
• Journal: Cell (Cell) Vol. 161 Issue 5 Pg. 1215-1228 (May 21 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 26000489 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Topics

• Cohort Studies
• Gene Expression Profiling (methods)
• Humans
• Male
• Mutation
• Neoplasm Metastasis (drug therapy, genetics, pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)