Prostate Adenocarcinoma Pan-1000 Meta-Cohort (Armenia et al. 2018)

Overview

prad_p1000 is a pan-1000 prostate cancer meta-cohort assembled by Armenia et al. (2018) by aggregating and uniformly re-analyzing whole-exome sequencing from 1,013 prostate tumor/normal pairs drawn from prior published cohorts. It comprises 680 primary (treatment-naive) and 333 metastatic castration-resistant prostate cancer (CRPC) tumors. The dataset is publicly available in cBioPortal at study ID prad_p1000. Uniform reprocessing used PICARD re-alignment, MuTect v1.1.6 (SNVs), Strelka v1.0.11 (indels), ReCapSeg + GISTIC 2.0 (copy number), and FACETS v0.5.10 (allele-specific CN / purity / ploidy).

Composition

• Cancer type: Prostate Adenocarcinoma (PRAD), OncoTree code PRAD.
• N = 1,013 tumor/normal WES pairs: 680 primary, 333 metastatic castration-resistant.
• Mean target coverage: 104.7x (tumor), 103.8x (normal); ContEst < 5% (mean 0.6%).
• Sources aggregated from multiple prior TCGA and non-TCGA WES studies, uniformly reprocessed.
• Validation cohorts: 706 advanced prostate cancers from msk_impact_2017; 204 prostate cancers from Foundation Medicine (phs001179).

Assays / panels (linked)

• whole-exome-seq
• mutect
• strelka
• facets
• gistic

Papers using this cohort

• PMID:29610475 — Armenia et al., discovery paper defining this cohort

Notable findings derived from this cohort

• 97 significantly mutated genes (SMGs) identified by MutSig2CV, including 70 not previously implicated in prostate cancer and 9 novel across all cancer types; most novel SMGs are mutated in fewer than 5% of tumors and required over 900 samples to detect PMID:29610475.
• Metastatic tumors carry higher non-synonymous mutation rate (mean 2.93 mut/Mb vs. 1.36 mut/Mb in primary, p<0.001) and higher copy-number burden PMID:29610475.
• CUL3 identified as a new SPOP-like prostate-cancer driver (1.3%, recurrent hotspot p.Met299Arg), mutually exclusive with SPOP mutations; validated in msk_impact_2017 (9 additional cases) PMID:29610475.
• Spliceosome pathway (SF3B1 1.1%, U2AF1 0.5%) nominated as a new recurrent prostate cancer pathway PMID:29610475.
• SPEN identified as a metastasis-enriched AR-pathway driver (2.4%, predominantly truncating, q=0.008) PMID:29610475.
• 20% of samples carry alterations in epigenetic/chromatin-remodeling genes; enriched in ETS-fusion-negative tumors and those lacking known drivers PMID:29610475.
• DNA-repair pathway altered in 16%; novel prostate-specific SMGs include MRE11 and PALB2; CDK12 mutations predominantly truncating with frequent biallelic inactivation PMID:29610475.

Sources

• cBioPortal study: prad_p1000 (http://www.cbioportal.org/study?id=prad_p1000)
• Armenia J, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018. PMID:29610475

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