MSK CRC IMPACT Cohort (2017)

Overview

Prospective targeted sequencing cohort of 1,134 colorectal adenocarcinomas assembled at Memorial Sloan Kettering Cancer Center using the MSK-IMPACT panel. The cohort comprises 1,011 tumors from 979 patients with metastatic CRC plus 123 tumors from 120 patients with early-stage CRC. This is one of the largest prospectively sequenced CRC cohorts and defines the landscape of microsatellite-stable (MSS), MSI-H/hypermutated, and POLE-mutant colorectal cancer in a clinical setting. Data are publicly available on cBioPortal (crc_msk_2017) and at European Variation Archive accession PRJEB23844. PMID:29316426

Composition

  • 1,134 colorectal adenocarcinomas: 1,011 tumors (478 primaries, 533 metastases) from 979 metastatic CRC patients, plus 123 tumors from 120 early-stage CRC patients. PMID:29316426
  • Cancer types: COADREAD (COAD and READ). PMID:29316426
  • Molecular subtypes: 1,027 MSS (90.6%), 99 MSI-H/hypermutated (8.7%), 8 POLE-mutant (0.7%); 4% of mCRC cases were MSI-H. PMID:29316426
  • Sidedness: Cohort annotated for primary tumor laterality; right-sided vs. left-sided comparisons are a major analytical axis. PMID:29316426
  • Tissue/procedure: 70% resection / 30% needle biopsy; 52% pre-treatment samples. Matched tumor/normal calling in a CLIA-certified lab. PMID:29316426
  • Median follow-up: 23.7 months for MSS early-stage; 28.6 months for MSS mCRC. PMID:29316426

Assays / panels (linked)

Papers using this cohort

  • PMID:29316426 — Yaeger et al. 2018, Cancer Cell — “Clinical sequencing defines the genomic landscape of metastatic colorectal cancer”

Notable findings derived from this cohort

  • 47 significantly recurrently mutated genes in MSS CRC identified via MutSig and MuSiC. Top frequencies: APC 79%, TP53 78%, KRAS 44%, PIK3CA 18%, SMAD4 16%. PMID:29316426
  • WNT pathway alterations reach 96% of CRCs when an intronic APC splice-acceptor variant (chr5:112151184 A>G) and large CTNNB1 exon-3 in-frame deletions are included. PMID:29316426
  • Right-sided MSS mCRC has shorter 5-year OS (45% vs. 67%, p<0.001), higher mutation burden, and enrichment of KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 vs. left-sided. PMID:29316426
  • 37% of left-sided MSS mCRC have no detectable mitogenic-signaling alteration, with higher expression of RTK ligands (amphiregulin, epiregulin, neuregulin, HGF) suggesting ligand-driven activation. PMID:29316426
  • Five genomic mitogenic-pathway subgroups (RTK-only, RAS-MAPK, PI3K, concurrent, none) were defined and largely explain the right-vs-left survival gap. PMID:29316426
  • Multivariate survival: APC alterations favorable (HR=0.57); BRAF (HR=2.02), KRAS (HR=1.40), and NRAS (HR=2.59) unfavorable; primary tumor side not significant after genomic adjustment. PMID:29316426
  • 86% of MSI-H/hypermutated vs. 37% of MSS mCRC harbored potentially actionable alterations per OncoKB. PMID:29316426

Sources

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