Metastatic Castration-Resistant Prostate Cancer FHCRC 2016 (Kumar et al.)

Overview

Rapid-autopsy multi-region genomic study of 63 men with metastatic castration-resistant prostate cancer (PRAD) enrolled in the University of Washington Prostate Cancer Donor Program. Tissue collected within 6 hours of death; 176 primary or metastatic tumors profiled by whole-exome sequencing, array CGH, and expression microarray. Established that metastases within a single patient are highly concordant for major oncogenic drivers, supporting single-biopsy clinical adequacy in mCRPC. Molecular profiling deposited at GEO accession GSE74685; registered in cBioPortal as prad_fhcrc. PMID:26928463

Composition

  • 63 men with mCRPC at rapid autopsy.
  • 176 primary or metastatic tumors:
    • WES: 141 tumors from 56 men (Nimblegen V2/V3 capture, Illumina HiSeq 2000, 50/100 bp PE).
    • Array CGH: 149 tumors from 60 men (Agilent 2×400K SurePrint G3 CGH; CBS segmentation; GISTIC 2.0).
    • Expression microarray: 171 tumors from 63 men (Agilent 44K).
  • Histology: 156 adenocarcinomas; 20 small-cell neuroendocrine tumors (from 2 men).
  • All men received androgen deprivation therapy (ADT); most also received a systemic chemotherapy (docetaxel) and an additional AR pathway-targeted agent.
  • 20/63 men were treated with carboplatin and analyzed for DNA-repair biomarker response. PMID:26928463

Assays / panels (linked)

Papers using this cohort

  • PMID:26928463 — Kumar et al., Nat Genet 2016: primary study; established intra-individual concordance of metastatic drivers and Fanconi anemia pathway as carboplatin response biomarker.

Notable findings derived from this cohort

  • Substantial inter-individual genomic diversity but limited intra-individual diversity: median 6.7% of CNA aberrations differed between tumors from the same patient vs 22.1% between different patients (P < 0.001) PMID:26928463.
  • AR amplification or mutation in 63% of men (vs rare in primary PC); 88% of patients had tumors with robust AR transcriptional activity despite prior AR-suppressive therapy PMID:26928463.
  • TMPRSS2-ERG status 100% concordant across metastases by FISH (53 tumors, 13 men); 94% concordant by array CGH PMID:26928463.
  • 5 men had hypermutated genomes with complex structural aberrations in MSH2 and MSH6; MMR deficiency apparent in matched primaries PMID:26928463.
  • Fanconi anemia pathway gene expression elevated in high-CCP (cell-cycle progression) tumors; RB1 loss associated with elevated CCP and 15-gene FA signature (r = 0.78, P < 0.001) PMID:26928463.
  • Men with somatic DNA-repair pathway aberration (FA-gene homozygous loss or ATM inactivation) had significantly longer time on carboplatin (Kaplan-Meier log-rank P = 0.02, n=20 carboplatin-treated) PMID:26928463.
  • Metastasis-private mutations compared against prad_tcga and prad_su2c_2015 — only 2/51 private mutations occurred at >5% frequency in those cohorts, arguing most are non-driver events PMID:26928463.
  • Used as a comparison mCRPC cohort (63 cases) in the MSK-IMPACT prostate cancer profiling study; HR gene alteration frequencies were cross-validated against this cohort PMID:28825054.
  • Used for cross-cohort correlation of the NOL10 cell-cycle signature (CCS) with the clinical cell-cycle-progression (CCP) score PMID:28927585.

Sources

  • cBioPortal study: prad_fhcrc
  • Molecular profiling data: GEO accession GSE74685
  • PMID:26928463 — Kumar A et al., “Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer.” Nat Genet 2016.

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