MET500 — Michigan Oncology Sequencing Metastatic Solid Tumors 2017 (Robinson et al.)

Overview

The MET500 cohort (also referred to as metastatic_solid_tumors_mich_2017 in cBioPortal) is a pan-cancer prospective cohort of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site, assembled under the Michigan Oncology Sequencing (Mi-Oncoseq) program. Robinson et al. performed paired tumor/normal whole-exome sequencing and poly(A)+/exome-capture transcriptomics alongside T-cell receptor β CDR3 deep sequencing to characterize the somatic, germline, fusion, and immune landscape of metastatic disease. The study established that metastatic tumors carry a higher mutation burden than matched primary cohorts, identified putative pathogenic germline variants in 12.2% of cases (75% in DNA-repair genes), and defined two transcriptional metastatic subtypes (EMT-like vs proliferative). Sequencing data are deposited in dbGaP (phs000673.v2.p1); data also accessible via the MET500 web portal (met500.path.med.umich.edu) PMID:28783718.

Composition

  • Total: 500 adult patients (537 biopsies / 556 enrolled; 93% complete-sequencing success rate); 258 male / 242 female; 460 (92%) Caucasian; median age 59 years (range 18–86).
  • Cancer types (n=20): Top three — 93 (18.6%) metastatic prostate (PRAD), 91 (18.2%) metastatic breast (BRCA), 42 (8.4%) soft-tissue sarcoma (SARCNOS); overall lineage MIXED.
  • Biopsy sites (>30 organs): 134 liver, 114 lymph node, 46 lung, 42 bone, 32 abdominal mass/ascites/pleural fluid.
  • Exome assay: Agilent SureSelect Human All Exon v4; mean target coverage 180× tumor / 120× normal; mean tumor content 62%.
  • RNA-seq: poly(A)+ and exome-capture on Illumina HiSeq 2000/2500 (40–50M paired reads); 868 transcriptome libraries from 496 tumors.
  • TCR-seq: T-cell receptor β CDR3 via Adaptive Biotechnologies immunoSEQ.
  • Bioinformatics: alignment to GRCh37/hg19 via Novoalign; SNV calling by VarScan2 v2.3.2; indels by Pindel; fusion calling via CODAC pipeline; RNA alignment by STAR to GRCh38/Gencode V23 (custom transcript reference) PMID:28783718.

Assays / panels (linked)

Papers using this cohort

  • PMID:28783718 — Robinson et al. 2017; inaugural description of the MET500 pan-cancer metastatic cohort (500 patients; WES + RNA-seq + TCR-seq).

Notable findings derived from this cohort

  • Mean of 119 somatic mutations per patient within targeted exome regions; mutation burden significantly elevated vs TCGA primaries for most cancer types, with the largest increase in tumor types with low primary-stage mutation burden (e.g., prostate, adrenal) PMID:28783718.
  • Most-altered tumor suppressors: TP53 266/500 (53.2%), CDKN2A 80 (16%), PTEN 79 (15.8%), RB1 68 (13.6%); most-altered oncogenes: PIK3CA 67 (13.4%), AR 63 (12.6%), KRAS 51 (10.2%) PMID:28783718.
  • Presumed pathogenic germline mutations (PPGM) in 12.2% of patients (61 individuals / 18 genes); 75% in DNA-repair genes — MUTYH n=10 (16%), BRCA2 n=9 (14%), CHEK2 n=9 (14%), BRCA1 n=5 (8%); PPGM odds significantly elevated vs ExAC controls (OR=3.00, 95% CI 2.28–3.9, P=1×10⁻¹³) PMID:28783718.
  • 199/496 tumors (39.8%) carried at least one putative pathogenic gene fusion; 12,027 unique fused gene pairs (mean 34/tumor); novel activating ALK, BRAF, and FGFR fusions with new partners PMID:28783718.
  • Two transcriptional metastatic subtypes: EMT-like (inflammation signatures) and proliferative (metabolism and stress response); subtype assignments only weakly tied to biopsy site or primary tissue; metastatic samples showed significant tissue-marker dedifferentiation vs normal/primary PMID:28783718.
  • RNA-seq-derived MImmScore (141 ESTIMATE immune-signature genes) correlated with TCR-β CDR3 sequencing; cancer types known to be infiltrated in localized stage (kidney, lung, melanoma) remained infiltrated at metastatic sites; composite “fully active” immune classification (TIL-5 + APC-1 + Tcell-1 cluster) correlated with PD-L1, HLA, granzyme expression, and a melanoma-derived clinical-response score PMID:28783718.
  • Note: cBioPortal study metastatic_solid_tumors_mich_2017 uses GRCh37/hg19 for DNA; RNA processed against GRCh38 with custom MOTR/Gencode V23 transcript reference PMID:28783718.

Sources

  • Robinson DR, Wu YM, Lonigro RJ, et al. Integrative clinical genomics of metastatic cancer. Nature. 2017;548(7667):297-303. PMID:28783718

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