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.
Cell. 2015 May 21 [Epub]
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
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Institute for Precision Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; New York Presbyterian Hospital, New York, NY 10021, USA; Meyer Cancer, Weill Medical College of Cornell University, New York, NY 10021, USA., Computational Biology Program, Public Health Sciences Division and Basic Science Division, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109, USA; Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA., Cancer Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research, London SM2 5NG, UK; Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London SM2 5NG, UK., Institute for Precision Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; New York Presbyterian Hospital, New York, NY 10021, USA; Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Meyer Cancer, Weill Medical College of Cornell University, New York, NY 10021, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Computational Biology Program, Public Health Sciences Division and Basic Science Division, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109, USA., Prostate Cancer Clinical Trials Consortium, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Department of Internal Medicine, Division of Hematology Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Interventional Radiology, Department of Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115, USA., Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Department of Musculoskeletal Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA., Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA., Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA., Department of Radiology, University of Washington, Seattle, WA 98109, USA., Department of Pathology, University of Washington Medical Center, Seattle, WA 98109, USA., Institute for Precision Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Laboratory of Computational Oncology, CIBIO, Centre for Integrative Biology, University of Trento, 38123 Mattarello TN, Italy., Institute for Precision Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Division of Interventional Radiology, Department of Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY 10021, USA; Meyer Cancer, Weill Medical College of Cornell University, New York, NY 10021, USA., Institute for Precision Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA; Department of Physiology & Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA., Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA., Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Institute for Precision Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA; Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA; Meyer Cancer, Weill Medical College of Cornell University, New York, NY 10021, USA., Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA., The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA; Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Meyer Cancer, Weill Medical College of Cornell University, New York, NY 10021, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: ., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: .