Robinson, D., Van Allen, E. M., Wu, Y. M., Schultz, N., Lonigro, R. J., Mosquera, J. M., Montgomery, B., Taplin, M. E., Pritchard, C. C., Attard, G., Beltran, H., Abida, W., Bradley, R. K., Vinson, J., Cao, X. H., Vats, P., Kunju, L. P., Hussain, M., Feng, F. Y., Tomlins, S. A., Cooney, K. A., Smith, D. C., Brennan, C., Siddiqui, J., Mehra, R., Chen, Y., Rathkopf, D. E., Morris, M. J., Solomon, S. B., Durack, J. C., Reuter, V. E., Gopalan, A., Gao, J. J., Loda, M., Lis, R. T., Bowden, M., Balk, S. P., Gaviola, G., Sougnez, C., Gupta, M., Yu, E. Y., Mostaghel, E. A., Cheng, H. H., Mulcahy, H., True, L. D., Plymate, S. R., Dvinge, H., Ferraldeschi, R., Flohr, P., Miranda, S., Zafeiriou, Z., Tunariu, N., Mateo, J., Perez-Lopez, R., Demichelis, F., Robinson, B. D., Schiffman, M., Nanus, D. M., Tagawa, S. T., Sigaras, A., Eng, K. W., Elemento, O., Sboner, A., Heath, E. I., Scher, H. I., Pienta, K. J., Kantoff, P., de Bono, J. S., Rubin, M. A., Nelson, P. S., Garraway, L. A., Sawyers, C. L., Chinnaiyan, A. M. (2015) Integrative Clinical Genomics of Advanced Prostate Cancer. CELL, 161 (5). pp. 1215-1228. ISSN 0092-8674

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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, beta-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.

Item Type:	Article
Authors (ICR Faculty only):	De Bono, Johann
All Authors:	Robinson, D., Van Allen, E. M., Wu, Y. M., Schultz, N., Lonigro, R. J., Mosquera, J. M., Montgomery, B., Taplin, M. E., Pritchard, C. C., Attard, G., Beltran, H., Abida, W., Bradley, R. K., Vinson, J., Cao, X. H., Vats, P., Kunju, L. P., Hussain, M., Feng, F. Y., Tomlins, S. A., Cooney, K. A., Smith, D. C., Brennan, C., Siddiqui, J., Mehra, R., Chen, Y., Rathkopf, D. E., Morris, M. J., Solomon, S. B., Durack, J. C., Reuter, V. E., Gopalan, A., Gao, J. J., Loda, M., Lis, R. T., Bowden, M., Balk, S. P., Gaviola, G., Sougnez, C., Gupta, M., Yu, E. Y., Mostaghel, E. A., Cheng, H. H., Mulcahy, H., True, L. D., Plymate, S. R., Dvinge, H., Ferraldeschi, R., Flohr, P., Miranda, S., Zafeiriou, Z., Tunariu, N., Mateo, J., Perez-Lopez, R., Demichelis, F., Robinson, B. D., Schiffman, M., Nanus, D. M., Tagawa, S. T., Sigaras, A., Eng, K. W., Elemento, O., Sboner, A., Heath, E. I., Scher, H. I., Pienta, K. J., Kantoff, P., de Bono, J. S., Rubin, M. A., Nelson, P. S., Garraway, L. A., Sawyers, C. L., Chinnaiyan, A. M.
Additional Information:	ISI Document Delivery No.: CJ0GA Times Cited: 0 Cited Reference Count: 64 Robinson, Dan Van Allen, Eliezer M. Wu, Yi-Mi Schultz, Nikolaus Lonigro, Robert J. Mosquera, Juan-Miguel Montgomery, Bruce Taplin, Mary-Ellen Pritchard, Colin C. Attard, Gerhardt Beltran, Himisha Abida, Wassim Bradley, Robert K. Vinson, Jake Cao, Xuhong Vats, Pankaj Kunju, Lakshmi P. Hussain, Maha Feng, Felix Y. Tomlins, Scott A. Cooney, Kathleen A. Smith, David C. Brennan, Christine Siddiqui, Javed Mehra, Rohit Chen, Yu Rathkopf, Dana E. Morris, Michael J. Solomon, Stephen B. Durack, Jeremy C. Reuter, Victor E. Gopalan, Anuradha Gao, Jianjiong Loda, Massimo Lis, Rosina T. Bowden, Michaela Balk, Stephen P. Gaviola, Glenn Sougnez, Carrie Gupta, Manaswi Yu, Evan Y. Mostaghel, Elahe A. Cheng, Heather H. Mulcahy, Hyojeong True, Lawrence D. Plymate, Stephen R. Dvinge, Heidi Ferraldeschi, Roberta Flohr, Penny Miranda, Susana Zafeiriou, Zafeiris Tunariu, Nina Mateo, Joaquin Perez-Lopez, Raquel Demichelis, Francesca Robinson, Brian D. Schiffman, Marc Nanus, David M. Tagawa, Scott T. Sigaras, Alexandros Eng, Kenneth W. Elemento, Olivier Sboner, Andrea Heath, Elisabeth I. Scher, Howard I. Pienta, Kenneth J. Kantoff, Philip de Bono, Johann S. Rubin, Mark A. Nelson, Peter S. Garraway, Levi A. Sawyers, Charles L. Chinnaiyan, Arul M. Stand Up To Cancer-Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant; NIH: Clinical Sequencing Exploratory Research (CSER) [UM1HG006508]; NIH: Early Detection Research Network grant [UO1 CA111275]; NIH: Prostate SPORE [P50 CA186786, P50 CA092629, P50 CA90381, P50 CA097186, P01 CA163227, R01 CA116337, R01 CA155169, R01 CA092629]; DoD [W81XWH-09-1-0147, DOD PC121341, PC131820]; Starr Cancer Consortium; Damon Runyon Cancer Research Foundation [CI-67-13]; PCF Young Investigator Award; NIH [1K08CA188615]; Prostate Cancer Foundation Young Investigator Awards; Movember Foundation; ECMC network from Cancer Research UK; Department of Health in the UK; BRC grant; Prostate Cancer UK, PCF We thank the affected individuals who participated in this study to better understand the feasibility and utility of precision medicine approaches for advanced prostate cancer. Individuals at our respective institutions who helped with this study are listed by institution. University of Michigan: Karen Giles, Lynda Hodges, Erica Rabban, Ning Yu, Fengyun Su, Rui Wang, Brendan Veeneman, and Moshe Talpaz. MSKCC: Brett Carver, Kristen Curtis, and Julie Filipenko. DFCI/Broad: Zhenwei Zhang, Daniele Depalo, and Joseph Kramkowski. University of Washington: Jina Taub, Hiep Nguyen, Colm Morrissey, and Robert Vessella. ICR/Royal Marsden: Suzanne Carreira, Ines Figueiredo, and Daniel Nava Rodrigues. This work was supported by a Stand Up To Cancer-Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SU2C-AACR-DT0712). The project was also supported by the following NIH awards: Clinical Sequencing Exploratory Research (CSER) UM1HG006508 (A.M.C.), Early Detection Research Network grant UO1 CA111275(A.M.C.), Prostate SPORE grants P50 CA186786 (A.M.C.), P50 CA092629 (H.I.S., C.L.S., and Y.C.), P50 CA90381 (P.K.), and P50 CA097186 (P.S.N., B.M., E.A.M., and L.D.T.), P01 CA163227 (P.S.N., S.P., R.K.B., H.D.), R01 CA116337 (M.A.R., H.B., F.D.), R01 CA155169 (C.L.S.), R01 CA092629, P50 CA092629 (H.I.S., C.L.S., and Y.C.), and R01 CA155169 (C.L.S.). This work was supported by the following DoD awards: W81XWH-09-1-0147 (PCCTC) and DOD PC121341 (H.B.). This work was also supported by the Starr Cancer Consortium (N.S., M.R., C.S., Y.C., L.A.G.). A.M.C. is an A. Alfred Taubman Scholar and an American Cancer Society Professor. H.B. is supported by Damon Runyon Cancer Research Foundation CI-67-13. C.P. is supported by a PCF Young Investigator Award and DoD PC131820. E.M.V. is supported by a NIH 1K08CA188615. E.M.V., N.S., and F.Y.F. are supported by Prostate Cancer Foundation Young Investigator Awards. The RM and ICR team is supported by the Movember Foundation and Prostate Cancer UK, PCF, the ECMC network from Cancer Research UK, the Department of Health in the UK, and BRC grant funding. 0 CELL PRESS CAMBRIDGE CELL
Uncontrolled Keywords:	ETS GENE FUSIONS INCREASED SURVIVAL MUTATIONS REARRANGEMENTS ENZALUTAMIDE CHEMOTHERAPY ABIRATERONE INHIBITION DISCOVERY HETEROGENEITY
Research teams:	ICR divisions > Cancer Therapeutics > Cancer Biomarkers ICR divisions > Clinical Studies > Cancer Biomarkers ICR divisions > Clinical Studies > Prostate Cancer Targeted Therapy Group
Depositing User:	Barry Jenkins
Date Deposited:	22 Jun 2015 13:40
Last Modified:	25 May 2017 15:27
URI:	http://publications.icr.ac.uk/id/eprint/14187

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