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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, ?-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.

SUBMITTER: Robinson D

PROVIDER: S-EPMC4484602 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Integrative clinical genomics of advanced prostate cancer.

Robinson Dan D Van Allen Eliezer M EM Wu Yi-Mi YM Schultz Nikolaus N Lonigro Robert J RJ Mosquera Juan-Miguel JM Montgomery Bruce B Taplin Mary-Ellen ME Pritchard Colin C CC Attard Gerhardt G Beltran Himisha H Abida Wassim W Bradley Robert K RK Vinson Jake J Cao Xuhong X Vats Pankaj P Kunju Lakshmi P LP Hussain Maha M Feng Felix Y FY Tomlins Scott A SA Cooney Kathleen A KA Smith David C DC Brennan Christine C Siddiqui Javed J Mehra Rohit R Chen Yu Y Rathkopf Dana E DE Morris Michael J MJ Solomon Stephen B SB Durack Jeremy C JC Reuter Victor E VE Gopalan Anuradha A Gao Jianjiong J Loda Massimo M Lis Rosina T RT Bowden Michaela M Balk Stephen P SP Gaviola Glenn G Sougnez Carrie C Gupta Manaswi M Yu Evan Y EY Mostaghel Elahe A EA Cheng Heather H HH Mulcahy Hyojeong H True Lawrence D LD Plymate Stephen R SR Dvinge Heidi H Ferraldeschi Roberta R Flohr Penny P Miranda Susana S Zafeiriou Zafeiris Z Tunariu Nina N Mateo Joaquin J Perez-Lopez Raquel R Demichelis Francesca F Robinson Brian D BD Schiffman Marc M Nanus David M DM Tagawa Scott T ST Sigaras Alexandros A Eng Kenneth W KW Elemento Olivier O Sboner Andrea A Heath Elisabeth I EI Scher Howard I HI Pienta Kenneth J KJ Kantoff Philip P de Bono Johann S JS Rubin Mark A MA Nelson Peter S PS Garraway Levi A LA Sawyers Charles L CL Chinnaiyan Arul M AM

Cell 20150501 5

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. ...[more]

PMID: 26000489

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Project description:BackgroundComprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging.Patients and methodsWe developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing.ResultsWe identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations.ConclusionsOur results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications.

Project description:It is understood that cancer is a clonal disease initiated by a single cell, and that metastasis, which is the spread of cancer from the primary site, is also initiated by a single cell. The seemingly natural capability of cancer to adapt dynamically in a Darwinian manner is a primary reason for therapeutic failures. Survival advantages may be induced by cancer therapies and also occur as a result of inherent cell and microenvironmental factors. The selected "more fit" clones outmatch their competition and then become dominant in the tumor via propagation of progeny. This clonal expansion leads to relapse, therapeutic resistance and eventually death. The goal of this study is to develop and demonstrate a more detailed clonality approach by utilizing integrative genomics.Patient tumor samples were profiled by Whole Exome Sequencing (WES) and RNA-seq on an Illumina HiSeq 2500 and methylation profiling was performed on the Illumina Infinium 450K array. STAR and the Haplotype Caller were used for RNA-seq processing. Custom approaches were used for the integration of the multi-omic datasets.Reported are major enhancements to CloneViz, which now provides capabilities enabling a formal tumor multi-dimensional clonality analysis by integrating: i) DNA mutations, ii) RNA expressed mutations, and iii) DNA methylation data. RNA and DNA methylation integration were not previously possible, by CloneViz (previous version) or any other clonality method to date. This new approach, named iCloneViz (integrated CloneViz) employs visualization and quantitative methods, revealing an integrative genomic mutational dissection and traceability (DNA, RNA, epigenetics) thru the different layers of molecular structures.The iCloneViz approach can be used for analysis of clonal evolution and mutational dynamics of multi-omic data sets. Revealing tumor clonal complexity in an integrative and quantitative manner facilitates improved mutational characterization, understanding, and therapeutic assignments.

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Integrative clinical genomics of advanced prostate cancer.

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Integrative clinical genomics of advanced prostate cancer.

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