Rhabdoid Cancer (MRT)

Overview

Rhabdoid cancer (MRT in OncoTree; also called malignant rhabdoid tumor of the kidney) is a rare, highly aggressive pediatric malignancy defined by biallelic inactivation of SMARCB1, a core subunit of the SWI/SNF chromatin-remodelling complex. In the OncoTree hierarchy it is a child of KIDNEY under the Rhabdoid Cancer main type. Extra-cranial MRT encompasses tumors of the kidney (majority), soft tissue, and liver; the liver variant is separately coded as MRTL. Despite a near-uniform single driver, MRT splits into reproducible miRNA, mRNA, and DNA-methylation sub-groups with distinct developmental and epigenetic signatures. Overall 4-year survival is ~23.2%.

Cohorts in the corpus

  • mrt_bcgsc_2016: 67 primary extra-cranial MRTs (58 kidney, 7 soft tissue, 2 liver) banked through the TARGET initiative and Children’s Oncology Group; 40 tumor/normal pairs for WGS; 66 miRNA-Seq; 40 RNA-Seq + WGBS; 35 H3K27me3 ChIP-Seq; 10 H3K27ac ChIP-Seq; data in NCBI dbGaP phs000470 PMID:26977886

Recurrent alterations

  • SMARCB1 — biallelic inactivation (mutations, deletions, somatic LOH) in 39/40 cases; the dominant and near-universal driver; loss causes downstream loss of H3K27me3 at homeobox promoters and gain of MRT-specific super-enhancers at HOX clusters PMID:26977886
  • SMARCA4 — sole driver in the one SMARCB1-intact case (somatic LOH plus germline one-base deletion) PMID:26977886
  • DSCAM — recurrent (2/40) heterozygous somatic missense substitutions (p.Val424Ile, p.Ser1354Thr); only non-SMARCB1 recurrently mutated gene; possibly passenger PMID:26977886
  • SPECC1L — intronic mutations in 6/40 cases associated with decreased expression; fusion partner in 4/7 SMARCB1-deletion-driven fusions PMID:26977886
  • KCNJ3 — intronic mutations in 8/40 cases associated with increased expression PMID:26977886
  • NF2, LIF — focally deleted in the only chromosome-22 deletions that spare SMARCB1 PMID:26977886
  • Quiet somatic genome: median 612.5 SNVs/case (0.231 mutations/Mb), 97.1% non-coding; median 5 non-synonymous substitutions/case PMID:26977886
  • PIPseq cohort included rhabdoid tumor cases; SMARCB1 homozygous deletion of chr22q11.23 with biallelic loss of expression identified as EZH2-inhibitor target PMID:28007021

Subtypes

  • miRNA sub-group 1 (n=57/66): clusters with normal cerebellum and TCGA pheochromocytoma/paraganglioma; lower miR-200 family expression (suggesting active EMT) PMID:26977886
  • miRNA sub-group 2 (n=9/66): clusters with synovial sarcomas; higher miR-200 family expression PMID:26977886
  • mRNA sub-group 1 (AT/RT-like): enriched for extra-renal cases; over-expresses BMP4, DLK1, MEOX2 PMID:26977886
  • mRNA sub-group 2 (RTK-like): over-expresses WNT5A, PCDH18, TCF21, MEIS1 PMID:26977886
  • Methylation sub-group A: higher promoter CGI methylation; enriched for age >1 year at diagnosis; gains methylation at tumor-suppressor promoters (RASSF1, IRX1, TWIST2, DLEC1, TBX5) PMID:26977886
  • Methylation sub-group B: clusters with hESC; enriched for age <1 year PMID:26977886

Therapeutic landscape

  • No prospective treatment data reported in the corpus PMID:26977886
  • Epigenetic vulnerabilities (H3K27me3 loss at homeobox promoters, MRT-specific HOX-cluster super-enhancers, HOTAIR over-expression) are candidate therapeutic dependencies PMID:26977886

Sources

  • PMID:26977886 — Chun et al., integrative multi-omic reference of 40 extra-cranial MRTs (WGS + WGBS + RNA-Seq + miRNA-Seq + ChIP-Seq)

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