Integrative clinical genomics of advanced prostate cancer

doi:10.1016/j.cell.2015.05.001

Multicenter Study

. 2015 May 21;161(5):1215-1228.

doi: 10.1016/j.cell.2015.05.001.

Integrative clinical genomics of advanced prostate cancer

Dan Robinson¹, Eliezer M Van Allen², Yi-Mi Wu¹, Nikolaus Schultz³, Robert J Lonigro⁴, Juan-Miguel Mosquera⁵, Bruce Montgomery⁶, Mary-Ellen Taplin⁷, Colin C Pritchard⁸, Gerhardt Attard⁹, Himisha Beltran¹⁰, Wassim Abida¹¹, Robert K Bradley¹², Jake Vinson¹³, Xuhong Cao¹⁴, Pankaj Vats⁴, Lakshmi P Kunju¹⁵, Maha Hussain¹⁶, Felix Y Feng¹⁷, Scott A Tomlins¹⁸, Kathleen A Cooney¹⁶, David C Smith¹⁶, Christine Brennan⁴, Javed Siddiqui⁴, Rohit Mehra¹, Yu Chen¹⁹, Dana E Rathkopf²⁰, Michael J Morris²⁰, Stephen B Solomon²¹, Jeremy C Durack²¹, Victor E Reuter²², Anuradha Gopalan²², Jianjiong Gao²³, Massimo Loda²⁴, Rosina T Lis²⁵, Michaela Bowden²⁶, Stephen P Balk²⁷, Glenn Gaviola²⁸, Carrie Sougnez²⁹, Manaswi Gupta²⁹, Evan Y Yu³⁰, Elahe A Mostaghel⁶, Heather H Cheng⁶, Hyojeong Mulcahy³¹, Lawrence D True³², Stephen R Plymate³⁰, Heidi Dvinge¹², Roberta Ferraldeschi⁹, Penny Flohr⁹, Susana Miranda⁹, Zafeiris Zafeiriou⁹, Nina Tunariu⁹, Joaquin Mateo⁹, Raquel Perez-Lopez⁹, Francesca Demichelis³³, Brian D Robinson⁵, Marc Schiffman³⁴, David M Nanus¹⁰, Scott T Tagawa¹⁰, Alexandros Sigaras³⁵, Kenneth W Eng³⁵, Olivier Elemento³⁶, Andrea Sboner³⁷, Elisabeth I Heath³⁸, Howard I Scher²⁰, Kenneth J Pienta³⁹, Philip Kantoff⁷, Johann S de Bono⁹, Mark A Rubin⁵, Peter S Nelson⁴⁰, Levi A Garraway², Charles L Sawyers⁴¹, Arul M Chinnaiyan⁴²

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ 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.
⁶ 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.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² Computational Biology Program, Public Health Sciences Division and Basic Science Division, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109, USA.
¹³ Prostate Cancer Clinical Trials Consortium, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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.
²⁰ 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.
²¹ Interventional Radiology, Department of Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²² Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²³ Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²⁴ 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.
²⁵ 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.
²⁶ 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.
²⁷ Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
²⁸ Department of Musculoskeletal Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA.
²⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
³⁰ Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA.
³¹ Department of Radiology, University of Washington, Seattle, WA 98109, USA.
³² Department of Pathology, University of Washington Medical Center, Seattle, WA 98109, USA.
³³ 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.
³⁴ 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.
³⁵ 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.
³⁶ Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA.
³⁷ 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.
³⁸ 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.
³⁹ The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁴⁰ 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.
⁴¹ 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: sawyersc@mskcc.org.
⁴² 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: arul@umich.edu.

PMID: 26000489
PMCID: PMC4484602
DOI: 10.1016/j.cell.2015.05.001

Multicenter Study

Integrative clinical genomics of advanced prostate cancer

Dan Robinson et al. Cell. 2015.

. 2015 May 21;161(5):1215-1228.

doi: 10.1016/j.cell.2015.05.001.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ 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.
⁶ 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.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² Computational Biology Program, Public Health Sciences Division and Basic Science Division, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109, USA.
¹³ Prostate Cancer Clinical Trials Consortium, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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.
²⁰ 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.
²¹ Interventional Radiology, Department of Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²² Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²³ Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²⁴ 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.
²⁵ 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.
²⁶ 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.
²⁷ Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
²⁸ Department of Musculoskeletal Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA.
²⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
³⁰ Department of Medicine and VAPSHCS, University of Washington, Seattle, WA 98109, USA.
³¹ Department of Radiology, University of Washington, Seattle, WA 98109, USA.
³² Department of Pathology, University of Washington Medical Center, Seattle, WA 98109, USA.
³³ 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.
³⁴ 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.
³⁵ 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.
³⁶ Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA.
³⁷ 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.
³⁸ 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.
³⁹ The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁴⁰ 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.
⁴¹ 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: sawyersc@mskcc.org.
⁴² 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: arul@umich.edu.

PMID: 26000489
PMCID: PMC4484602
DOI: 10.1016/j.cell.2015.05.001

Erratum in

Cell. 2015 Jul 16;162(2):454

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.

PubMed Disclaimer

Figures

**Figure 1. Overview of the SU2C-PCF IDT multi-institutional clinical sequencing of mCRPC project**
A, Schema of multi-institutional clinical sequencing project work flow. B, Clinical trials associated with the SU2C-PCF mCRPC project. C, Biopsy sites of the samples used for clinical sequencing. D, Histopathology of the cohort. Representative images of morphological analysis of mCRPC are shown along with prevalence in our cohort.

**Figure 2. Integrative landscape analysis of somatic and germline aberrations in metastatic CRPC obtained through DNA and RNA sequencing of clinically obtained biopsies**
Columns represent individual patients and rows represent specific genes grouped in pathways. Mutations per Mb shown in the upper histogram while incidence of aberrations in the cohort is in the right histogram. Copy number variations (CNVs) common to mCRPC are shown in in the lower matrix with pink representing gain and light blue representing loss. Color legend of the aberrations represented including amplification, 2 copy loss, 1 copy loss, copy neutral loss of heterozygosity (LOH), splice site mutation, frameshift mutation, missense mutation, in-frame indel, and gene fusion. Cases with more aberration in a gene are represented by split colors.

**Figure 3. Classes of genomic aberrations seen in mCPRC**
A, Copy number landscape of the SU2C-PCF mCRPC cohort. Individual chromosomes are represented by alternating colors and key aberrant genes are indicated. B, The gene fusion landscape of mCRPC. Pie chart of all driver fusions identified and the box plot represents specific ETS fusions. C, Mutations enriched in mCRPC relative to hormone naïve primary prostate cancer. Primary prostate cancer data derived from published studies (Barbieri et al., 2012) (TCGA, Provisional 2015). Level of CRPC enrichment represented by the×axis and MutSig CRPC significance analysis provided by the y axis. Diameters are proportional to the number of cases with the specific aberration. Genes of interest are highlighted. D, Classes of driver aberrations identified in mCRPC. E, Classes of clinically actionable mutations identified in mCRPC.

**Figure 4. Aberrations in the AR pathway found in mCRPC**
A, Cases with aberrations in the AR pathway. Case numbering as in Fig. 2. B, Key genes found altered in the AR pathway of mCRPC. DHT, dihydrotestosterone. C, Point mutations identified in AR. Amino acids altered are indicated. NTAD, N-terminal activation. DBD, DNA-binding. LBD, ligand binding. D, Splicing landscape of AR in mCRPC. Specific splice variants are indicated by exon boundaries and junction read level provided. SU2C, this mCRPC cohort. PRAD tumor, primary prostate cancer from the TCGA. PRAD normal, benign prostate from the TCGA. E, Homozygous deletion of *ZBTB16*. Copy number plots with×axis representing chromosomal location and the y axis referring to copy number level. Red outline indicates region of *ZBTB16* homozygous loss.

**Figure 5. Aberrations in the PI(3)K pathway found in mCRPC**
A, Cases with aberrations in the PIK3 pathway. Case numbering as in Fig. 2. B, Point mutations identified in PIK3CB. Amino acids altered are indicated. Analogous, recurrent COSMIC mutations in PIK3CA are shown as expansion views. C, Outlier expression of PK3CA in CRPC case harboring the TBL1XR1-PIK3CA gene fusion. Structure of the gene fusion is inset. UTR, untranslated region. CDS, coding sequence. D. As in C, except for PIK3CB and the ACPP-PIK3CB gene fusion.

**Figure 6. Aberrations in the WNT pathway found in mCRPC**
A, Cases with aberrations in the WNT pathway. Case numbering as in Fig. 2. B, Aberrations identified in APC and CTNNB1. Amino acids altered are indicated. ARM, armadillo repeat. Phos, phosphorylation domain. TAD, trans-activating domain. EB1, end binding protein-1 domain. CC, coiled coil. C, Outlier expression of *RSPO2* in CRPC and the *GRHL2-RSPO2* gene fusion. RNA-seq expression across our CRPC cohort. Structure of the gene fusion is inset. UTR, untranslated region. CDS, coding sequence.

**Figure 7. Aberrations in the DNA repair pathway found in mCRPC**
A, Cases with aberrations in the DNA repair pathway. Case numbering as in Fig. 2. B, Aberrations identified in BRCA2, ATM and BRCA1. Amino acids altered are indicated. HELC, helical domain. OB, oligonucleotide binding fold. FAT, FRAP-ATM-TRRAP domain. PIK3c, PI3 kinase domain. CC, coiled coil. BRC, Brca repeat. C, Microsatellite instability analysis of representative hypermutated CRPC cases and non-hypermutated cases.

See this image and copyright information in PMC

Comment in

Building a hit list for the fight against metastatic castration resistant prostate cancer.
Strope JD, Price DK, Figg WD. Strope JD, et al. Cancer Biol Ther. 2016;17(3):231-2. doi: 10.1080/15384047.2016.1139270. Epub 2016 Jan 29. Cancer Biol Ther. 2016. PMID: 26822877 Free PMC article.
Commentary on "Integrative clinical genomics of advanced prostate cancer". Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM.Cell. 21 May 2015;161(5):1215-1228.
Freedland SJ, Aronson WJ. Freedland SJ, et al. Urol Oncol. 2017 Aug;35(8):535. doi: 10.1016/j.urolonc.2017.05.010. Epub 2017 Jun 13. Urol Oncol. 2017. PMID: 28623072

Cited by

USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer.
Li S, Xiong S, Li Z, Yang L, Yang H, Xiong J, Pan W, Guo J, Xu S, Fu B. Li S, et al. Cell Death Dis. 2024 Nov 5;15(11):790. doi: 10.1038/s41419-024-07117-3. Cell Death Dis. 2024. PMID: 39500888 Free PMC article.
Cases of consecutive ductal adenocarcinoma of the prostate carrying HRR mutation: case series and literature review.
Han W, Rexiati N, Wang Y, Liu T, Luo Y, Yang Z. Han W, et al. Oxf Med Case Reports. 2024 Oct 26;2024(10):omae124. doi: 10.1093/omcr/omae124. eCollection 2024 Oct. Oxf Med Case Reports. 2024. PMID: 39464223 Free PMC article. No abstract available.
Contemporary Update on Clinical and Experimental Prostate Cancer Biomarkers: A Multi-Omics-Focused Approach to Detection and Risk Stratification.
Hachem S, Yehya A, El Masri J, Mavingire N, Johnson JR, Dwead AM, Kattour N, Bouchi Y, Kobeissy F, Rais-Bahrami S, Mechref Y, Abou-Kheir W, Woods-Burnham L. Hachem S, et al. Biology (Basel). 2024 Sep 25;13(10):762. doi: 10.3390/biology13100762. Biology (Basel). 2024. PMID: 39452071 Free PMC article. Review.
Synergistic effects of bloom helicase (BLM) inhibitor AO/854 with cisplatin in prostate cancer.
Ma X, Tian F, Xiao Y, Huang M, Song D, Chen X, Xu H. Ma X, et al. Sci Rep. 2024 Oct 23;14(1):24962. doi: 10.1038/s41598-024-75938-5. Sci Rep. 2024. PMID: 39438537 Free PMC article.
Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey.
McManus HD, Dorff T, Morgans AK, Sartor O, Shore N, Armstrong AJ. McManus HD, et al. Prostate Cancer Prostatic Dis. 2024 Oct 17. doi: 10.1038/s41391-024-00906-z. Online ahead of print. Prostate Cancer Prostatic Dis. 2024. PMID: 39420184 Review.

See all "Cited by" articles

References

1. ACS. Cancer Facts and Figures 2015. 2015
1. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. The New England journal of medicine. 2014;371:1028–1038. - PMC - PubMed
1. Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–282. - PMC - PubMed
1. Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, Rene-Corail F, et al. Integrated genomic characterization of adrenocortical carcinoma. Nature genetics. 2014;46:607–612. - PubMed
1. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, Park K, Kitabayashi N, Macdonald TY, Ghandi M, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–677. - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

[1] ACS. Cancer Facts and Figures 2015. 2015

[2] ACS. Cancer Facts and Figures 2015. 2015

[3] Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. The New England journal of medicine. 2014;371:1028–1038. - PMC - PubMed

[4] Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. The New England journal of medicine. 2014;371:1028–1038. - PMC - PubMed

[5] Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–282. - PMC - PubMed

[6] Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–282. - PMC - PubMed

[7] Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, Rene-Corail F, et al. Integrated genomic characterization of adrenocortical carcinoma. Nature genetics. 2014;46:607–612. - PubMed

[8] Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, Rene-Corail F, et al. Integrated genomic characterization of adrenocortical carcinoma. Nature genetics. 2014;46:607–612. - PubMed

[9] Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, Park K, Kitabayashi N, Macdonald TY, Ghandi M, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–677. - PMC - PubMed

[10] Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, Park K, Kitabayashi N, Macdonald TY, Ghandi M, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–677. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Integrative clinical genomics of advanced prostate cancer

Affiliations

Integrative clinical genomics of advanced prostate cancer

Authors

Affiliations

Erratum in

Abstract

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials

Miscellaneous

Erratum in

Abstract

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials

Miscellaneous