Prostate Cancer — Michigan WES (prad_mich)

Overview

A cohort assembled by the University of Michigan comprising 50 lethal metastatic castration-resistant prostate cancers (CRPCs) obtained at rapid autopsy (heavily pretreated, including 3 foci from the same patient) and 11 treatment-naive high-grade localized prostate cancers. An additional screening cohort of 101 localized and 46 CRPCs (total n=147) was used for FOXA1 analysis. CHD1 findings were validated across 13 independent DNA and RNA-based studies totaling 954 prostate cancers. Methods included whole-exome sequencing, array CGH, gene expression profiling, and transcriptome sequencing.

Composition

  • 50 metastatic CRPC tumors (rapid autopsy, heavily pretreated).
  • 11 treatment-naive high-grade localized prostate cancers.
  • Extended cohort: 147 total for FOXA1 analysis; 954 across 13 studies for CHD1 validation.
  • Cancer type: PRAD (prostate adenocarcinoma).
  • Key clinical fields: ETS fusion status, castration resistance, CHD1 deletion status.

Assays / panels (linked)

  • whole-exome-seq — primary mutation discovery.
  • Array CGH — copy-number profiling.
  • Transcriptome sequencing — fusion gene detection.
  • Gene expression profiling — AR pathway activity.

Papers using this cohort

  • PMID:22722839 — Integrative clinical genomics of advanced prostate cancer (Grasso et al., 2012).
  • PMID:26855148 — Beltran et al. 2016, Nature Medicine: used as external validation cohort for NEPC classifier; up to 8% of metastatic cases across prad_mich/prad_tcga/prad_su2c_2015 scored NEPC-high.

Notable findings derived from this cohort

  • Nine significantly mutated genes identified (FDR ≤ 0.10): TP53, AR, ZFHX3, RB1, PTEN, APC, KMT2D, OR5L1, CDK12 PMID:22722839.
  • CHD1 focal deletion/mutation in 8% of prostate cancers; 96% of CHD1-deleted cases were ETS fusion-negative (p<0.0001 across 954 tumors) PMID:22722839.
  • FOXA1 mutations (3.4% of cases) cluster in the C-terminal transactivation domain, repressing the AR transcriptional program and increasing xenograft tumor growth PMID:22722839.
  • TMPRSS2:ERG fusion present in the majority of ETS+ cases; ETS2 deleted in ~1/3 of CRPCs PMID:22722839.
  • Overall mutation rate in CRPC is low (2.00/Mb), confirming monoclonal origin; genomic complexity arises primarily from copy-number alterations and rearrangements PMID:22722839.
  • Used as an external validation cohort (Grasso et al. Michigan CRPC cases) for the NEPC classifier; up to 8% of metastatic samples across prad_mich, prad_tcga, and prad_su2c_2015 scored NEPC-high on pathology re-review PMID:26855148
  • Used (Grasso et al. / GSE35988, n=28 normal / 59 primary / 35 metastasis) to demonstrate elevated NOL10 mRNA in metastases relative to normals and primaries, and for Kaplan-Meier overall survival analysis (high NOL10 HR=2.20, 95% CI 1.03–4.69, P=0.034) PMID:28927585.

Sources

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