Prostate Adenocarcinoma — Broad/Cornell (Baca 2013)

Overview

Whole-genome sequencing study of 57 prostate cancers by Baca et al. (Cell 2013), focused on characterizing complex chromosomal rearrangements (“chromoplexy”) and their role in driver gene co-disruption and tumor evolution. BAM, RNA-seq, and SNP-array data deposited at dbGaP phs000447.v1.p1. PMID:23622249

Composition

  • 55 treatment-naïve primary PRAD adenocarcinomas spanning Gleason score 6–9 and pathological stages pT2N0–pT4N1, plus 2 neuroendocrine (PRNE) metastases arising after castration-based therapy. PMID:23622249
  • Extended cohort of 199 prostate adenocarcinomas used for SCNA recurrence and GISTIC analysis (this study combined with PMID:22610119). PMID:23622249

Assays / panels (linked)

Papers using this cohort

  • PMID:23622249 — Baca et al., “Punctuated Evolution of Prostate Cancer Genomes,” Cell 2013.

Notable findings derived from this cohort

  • Chromoplectic chains of ≥5 rearrangements (≥10 breakpoints) detected in 50/57 tumors (88%); 39% of rearrangements participated in chains vs. 2.8% in simulated controls (p<10⁻⁴); events span multiple chromosomes simultaneously, distinct from chromothripsis. PMID:23622249
  • ETS+ tumors show more inter-chromosomal chromoplexy in transcriptionally active regions (androgen receptor-coupled); ETS−/CHD1del tumors show intra-chromosomal rearrangements in GC-poor heterochromatin. PMID:23622249
  • 15/26 (58%) ERG-positive cases acquired the TMPRSS2–ERG fusion within a chromoplexy chain; chromoplexy coordinately disrupts multiple tumor suppressors in a single event — e.g., PTEN (9 cases), NKX3-1 (8 cases), TP53 (4 cases). PMID:23622249
  • CLONET-derived clonal ordering establishes a consensus progression path: early NKX3-1 deletion and TMPRSS2–ERG fusion → intermediate CDKN1B/TP53 loss → late PTEN deletion. PMID:23622249
  • Chromoplexy is not prostate-specific: ChainFinder detected chains of ≥5 rearrangements in melanoma, NSCLC, HNSC, and breast adenocarcinoma across an additional 59 genomes. PMID:23622249
  • Gleason grade tracks genomic derangement: tumors with predominant Gleason pattern 4 had more recurrent SCNAs than pattern 3 tumors (p=0.0059, 199-tumor cohort), independent of overall SCNA load, purity, and mutation burden. PMID:23622249

Sources

  • dbGaP: phs000447.v1.p1
  • DOI: 10.1016/j.cell.2013.03.021

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