Integrative clinical genomics of advanced prostate cancer

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. TomlinsKathleen 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1347 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1215-1228
Number of pages14
JournalCell
Volume161
Issue number5
DOIs
StatePublished - May 30 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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