MSK-IMPACT Prostate Cancer Clinical Sequencing Cohort 2017 (Abida et al.)

Overview

The MSK-IMPACT prostate cancer cohort is a prospective clinical sequencing study of 504 tumors from 451 patients with prostate adenocarcinoma spanning the full clinical spectrum — locoregional, metastatic noncastrate, and metastatic castration-resistant prostate cancer (mCRPC) — conducted at Memorial Sloan Kettering Cancer Center. Abida et al. applied the MSK-IMPACT hybridization-capture targeted DNA panel (>300 cancer-related genes), with paired germline analysis in 221 patients. The study identified potentially actionable alterations in 36% of patients (per OncoKB annotation) and established a 27% combined germline-or-somatic alteration rate in DDR genes (BRCA2, BRCA1, ATM, CHEK2), arguing for routine paired germline + somatic profiling as standard of care in advanced PRAD. Released as prad_mskcc_2017 on cBioPortal PMID:28825054.

Composition

  • Patients: 451; tumors profiled: 504 (44 patients had >1 tumor sequenced).
  • Disease-state composition (last known): 348 metastatic (77%), 53 biochemically recurrent (12%), 50 locoregional (11%).
  • Disease-state at tissue acquisition (504 tumors): 140 locoregional, 51 metastatic noncastrate prostate, 54 metastatic noncastrate metastasis sites, 95 mCRPC prostate, 164 mCRPC metastasis sites.
  • Metastatic biopsy sites: lymph node 45%, bone 22%, liver 14%, lung 5%, other soft tissue 14%.
  • Sequencing success rate: 504/746 (68%); bone and lung samples most challenging (42–52% success).
  • Assay: MSK-IMPACT hybridization-capture targeted DNA panel (>300 cancer-related genes) for SNVs, indels, somatic copy number alterations, and structural rearrangements; matched normal blood for germline filtering.
  • Germline analysis: 221 patients consented to germline analysis of 76 known cancer-predisposing genes.
  • Clonality: estimated via cancer cell fraction with the FACETS algorithm.
  • Actionability annotation: OncoKB.
  • Comparison cohorts: prad_su2c_2015 and prad_tcga_pub PMID:28825054.

Assays / panels (linked)

Papers using this cohort

  • PMID:28825054 — Abida et al. 2017; inaugural clinical description of the MSK-IMPACT prostate cohort, defining DDR alteration prevalence and disease-state enrichment patterns across the spectrum of prostate cancer.

Notable findings derived from this cohort

  • Mutation burden increases with castration resistance: mean nonsynonymous mutations/megabase rose from 1.74 (locoregional) to 4.02 (mCRPC), P<0.001; metastatic noncastrate tumors similar to locoregional (2.08 mut/Mb) PMID:28825054.
  • Somatic homologous recombination (HR) gene alterations in 22% of patients: BRCA2 7%, CDK12 7%, ATM 5%, FANCA 3%, PALB2 2%, BRCA1 1%, RAD50 1% PMID:28825054.
  • Germline pathogenic alterations in 19% of the 221 consented patients: BRCA2 9%, CHEK2 4%, ATM 2%, BRCA1 1%; combined germline-or-somatic DDR alteration rate 27% in the four canonical genes PMID:28825054.
  • mCRPC-enriched alterations vs locoregional: AR (2%→52%), TP53 (27%→48%), PTEN (12%→29%), RB1 (2%→18%), ATM (2%→11%), APC (4%→15%), CDK12 (4%→11%) PMID:28825054.
  • SPOP alterations enriched in earlier disease states (locoregional 12%→mCRPC 5%), suggesting potential androgen-deprivation sensitivity (functional validation pending) PMID:28825054.
  • APC enriched specifically in metastatic disease states relative to locoregional; ATM specifically enriched in mCRPC vs metastatic noncastrate — implicating distinct roles in metastasis vs castration resistance PMID:28825054.
  • TP53 and somatic BRCA2 alterations were present early and clonal (cancer cell fraction>0.9) in primary tumors of patients who later developed metastasis; AR alterations and PIK3CA E545K acquired late PMID:28825054.
  • OncoKB-annotated actionability: 36% of patients carried at least one potentially actionable alteration; MMR gene alterations in 3% produce hypermutator phenotype, nominating PD-1 blockade candidacy PMID:28825054.

Sources

  • Abida W, Armenia J, Gopalan A, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precision Oncology. 2017;1:1-16. PMID:28825054

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