Malignant Rhabdoid Tumor BCGSC 2016 (Chun et al.)

Overview

Integrative multi-omic reference landscape of 40 extra-cranial malignant rhabdoid tumors (MRT) — primarily pediatric kidney and soft-tissue cases — banked through the National Wilms Tumor Study Group 5 / Children’s Oncology Group (COG) AREN03B2 protocols and analyzed at the BC Cancer Genome Sciences Centre. The cohort combines whole-genome sequencing, whole-genome bisulfite sequencing (WGBS), RNA-Seq, miRNA-Seq, and H3K27me3/H3K27ac ChIP-Seq to characterize the molecular sub-groups and epigenetic architecture of MRT despite the near-uniform SMARCB1 driver. Sequencing reads and analyzed files deposited at NCBI dbGaP (phs000470) and the TARGET data portal. PMID:26977886

Composition

  • 40 tumor/normal pairs (WGS; median tumor content 88.0% by APOLLOH).
  • 66 primary MRTs profiled by miRNA-Seq (58 kidney, 7 soft tissue, 2 liver).
  • 40 matched normals: 16 adjacent kidney tissue, 24 peripheral blood.
  • Cancer types: rhabdoid tumor of the kidney (MRT) and extra-renal/liver MRT (MRTL).
  • Age range: predominantly <2 years (pediatric); one sub-group enriched for patients >1 year.
  • Multiple supplemental assays: 40 MRT + 3 MRT cell lines + 3 hESC lines + 4 NPCs (WGBS); 35 primary MRTs + cell lines + normals (H3K27me3 ChIP-Seq); 10 MRT + comparators (H3K27ac ChIP-Seq). PMID:26977886

Assays / panels (linked)

  • whole-genome-seq — 40 tumor/normal pairs; somatic SNV/indel and structural variant calling.
  • whole-genome-bisulfite-seq — WGBS on 40 MRT + 3 MRT cell lines + 3 hESC + 4 NPCs; promoter CpG-island methylation clustering.
  • rna-seq — 40 MRT + 3 hESC + 4 fetal cerebellum normals; mRNA sub-group discovery.
  • mirna-seq — 66 primary MRTs; clustering against TCGA and normal references (11,819 cases, 37 cancer types, 27 normal tissues).
  • chip-seq — H3K27me3 (35 MRT + 3 cell lines + 2 hESC + 2 fetal brain + 2 NPC); H3K27ac (10 MRT + 3 cell lines + 3 hESC + 1 fetal brain).

Papers using this cohort

  • PMID:26977886 — Chun et al., Nat Genet 2016: primary discovery study; integrative epigenomic and multi-omic reference for extra-cranial MRT.

Notable findings derived from this cohort

  • SMARCB1 biallelic inactivation in 39/40 cases; the single SMARCB1-intact case carried somatic LOH plus a germline one-base SMARCA4 deletion; median 612.5 somatic SNVs per case (0.231 mutations/Mb), confirming quiet genomes outside the SWI/SNF driver PMID:26977886.
  • DSCAM was the only recurrent non-SMARCB1 non-synonymous target (2/40 cases; flagged as possibly passenger) PMID:26977886.
  • Chromosome 22 dominated structural variation: 9/15 recurrent CNA loci and 22/26 verified gene fusions involve chr22; 7 fusions arise as direct consequences of SMARCB1 deletion, with SPECC1L as the most common fusion partner PMID:26977886.
  • miRNA clustering against TCGA/normals split 66 MRTs into a large group clustering with normal cerebellum and TCGA pheochromocytoma/paraganglioma and a smaller group (n=9) clustering with synovial sarcomas, linking MRT to neural-crest lineages PMID:26977886.
  • mRNA NMF sub-group 1 (enriched for extra-renal tumors) is more AT/RT-like; sub-group 2 is more RTK-like (one-sided Fisher p = 1.193e-13 vs Grupenmacher 2013 markers) PMID:26977886.
  • Two methylation sub-groups: sub-group A (higher CGI methylation) enriched for patients >1 year; MRT-specific super-enhancers cover HOXA, HOXB, HOXC, HISTH1/HISTH2 clusters and the HOTAIR lncRNA; 158 promoters show loss of H3K27me3 enriched for homeobox/HOX terms (FDR 4.17e-44) PMID:26977886.

Sources

  • NCBI dbGaP: phs000470
  • TARGET data portal: additional analyzed matrices
  • PMID:26977886 — Chun HE et al., “Genome-wide profiles of extra-cranial malignant rhabdoid tumors reveal heterogeneity and dysregulated developmental pathways.” Nat Genet 2016.

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