A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation

Mod Pathol. 2020 Mar;33(3):404-419. doi: 10.1038/s41379-019-0323-8. Epub 2019 Aug 5.

Abstract

Rhabdomyosarcomas with TFCP2 fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n = 12/14) and soft tissue (n = 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n = 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). ALK upregulation was frequently associated with an internal deletion at genomic level. TFCP2 was fused in 5' either to EWSR1 (n = 6) or FUS (n = 8). EWSR1 was involved in both soft tissue cases. FISH with TFCP2 break-apart probe was positive in all tested cases (n = 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions. FET-TFCP2 rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged, 80 and over
  • Anaplastic Lymphoma Kinase / genetics*
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Child
  • DNA-Binding Proteins / genetics*
  • Epithelioid Cells / pathology*
  • Female
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Molecular Diagnostic Techniques
  • Phenotype
  • Prognosis
  • Prospective Studies
  • Retrospective Studies
  • Rhabdomyosarcoma / chemistry
  • Rhabdomyosarcoma / genetics*
  • Rhabdomyosarcoma / mortality
  • Rhabdomyosarcoma / pathology*
  • Transcription Factors / genetics*
  • Up-Regulation
  • Young Adult

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • TFCP2 protein, human
  • Transcription Factors
  • ALK protein, human
  • Anaplastic Lymphoma Kinase