Prostate Adenocarcinoma SU2C / PCF 2015 (Robinson et al.)

Overview

Prospective integrative clinical sequencing cohort of 150 men with metastatic castration-resistant prostate cancer (mCRPC), assembled by the SU2C–PCF International Dream Team and published in Cell 2015 (PMID:26000489). All cases received whole-exome sequencing (WES) and paired transcriptome sequencing of biopsies from bone or soft tissue metastases, along with matched germline. Eight clinical sites contributed; analysis was performed at the Broad Institute and University of Michigan. The study was powered to compare mCRPC with 440 primary prostate cancer exomes to identify selectively enriched alterations in the metastatic castration-resistant setting.

Composition

  • N = 150 men with mCRPC who met ≥20% tumor content threshold (from 189 enrolled, 175 sequenced after pathology review).
  • Cancer type: PRAD (mCRPC).
  • Biopsy sites: lymph node (42%), bone (28.7%), liver (12.7%), other soft tissues (16.7%).
  • Histology: 96.4% high-grade prostate adenocarcinoma; 2.9% with neuroendocrine differentiation; 0.7% small-cell neuroendocrine features.
  • Clinical context: patients being considered for abiraterone or enzalutamide as standard of care, or as part of clinical trials including PARP inhibitors and aurora-kinase inhibitors.

Assays / panels (linked)

  • whole-exome-seq — SureSelect Exome v4; mean target coverage 160× (tumor) / 100× (normal). Reference genome hg19/GRCh37.
  • rna-seq — paired-end on Illumina HiSeq 2500 (2×100 nt, ~50M paired reads); FPKM via Cufflinks; fusion detection via tophat-fusion.
  • mutect — somatic mutation calling.
  • mutsig — recurrence analysis.

Papers using this cohort

  • PMID:26000489 — Robinson et al., Cell 2015: integrative clinical genomics of 150 mCRPC; primary discovery study for this cohort.
  • PMID:26855148 — Beltran et al. 2016, Nature Medicine: used as external validation cohort for the 70-gene NEPC classifier; up to 8% of metastatic cases scored NEPC-high.
  • PMID:26928463 — Kumar et al., Nat Genet 2016: queried to verify metastasis-private mutations from prad_fhcrc rapid-autopsy cohort are non-driver.

Notable findings derived from this cohort

  • 89% of mCRPC cases harbored a clinically actionable aberration: AR alterations 62.7%, other cancer-gene alterations 65%, actionable pathogenic germline 8%. PMID:26000489
  • DNA repair pathway (including BRCA2, BRCA1, ATM) biallelic loss in 19.3% of cases; 5.3% carried germline BRCA2 with somatic second hit — supporting PARP inhibitor candidacy and germline testing in mCRPC. PMID:26000489
  • TP53 most selectively mutated gene in mCRPC vs. primary prostate cancer (q<0.001); AR, KMT2D, APC, BRCA2, GNAS also selectively enriched (q<0.1). PMID:26000489
  • Novel recurrent focal homozygous deletion at chr11q23 narrowed to ZBTB16 in 8 cases (5%) — androgen-regulated gene linked to MAPK upregulation and androgen resistance. PMID:26000489
  • Novel activating PIK3CB mutations at positions equivalent to canonical PIK3CA hotspots, co-occurring with PTEN loss; activating PIK3CB fusions also identified — nominating PIK3CB-specific inhibitors. PMID:26000489
  • ETS fusions (predominantly ERG) in 56% of mCRPC cases; WNT pathway (APC/CTNNB1/RNF43/ZNRF3/RSPO2) in 18%; recurrent BRAF and RAF1 fusions in ~3%. PMID:26000489
  • Used as an external validation cohort (n=150 mCRPC) for the 70-gene NEPC classifier; up to 8% of metastatic cases scored NEPC-high and 0% of treatment-naïve adenocarcinomas did PMID:26855148
  • Used alongside prad_tcga to assess frequency of metastasis-private mutations from the prad_fhcrc rapid-autopsy cohort; only 2/51 patient-99-091 private mutations occurred at >5% frequency, arguing most are non-driver PMID:26928463
  • Served as a comparison cohort (150 mCRPC cases) alongside prad_tcga_pub in the MSK-IMPACT prostate cancer prospective profiling study; used to contextualize DDR gene alteration frequencies and disease-state enrichment patterns PMID:28825054.

Sources

  • cBioPortal study: prad_su2c_2015
  • PMID:26855148 — Beltran et al. 2016, Nature Medicine: NEPC classifier validation using this cohort.

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