SRF-FOXO1 and SRF-NCOA1 Fusion Genes Delineate a Distinctive Subset of Well-differentiated Rhabdomyosarcoma

Am J Surg Pathol. 2020 May;44(5):607-616. doi: 10.1097/PAS.0000000000001464.

Abstract

Rhabdomyosarcoma (RMS) encompasses a heterogenous collection of tumors in which new groups have recently been identified that improved the World Health Organization (WHO) classification. While performing RNA-sequencing in our routine practice, we identified 3 cases of well-differentiated RMS harboring new fusion genes. We also analyzed these tumors through array-comparative genomic hybridization. Clinically, these tumors were deep paraspinal tumors, occurring in neo-nat and young children. The patients underwent resection and adjuvant therapy. At the time of last follow-up (ranging from 12 to 108 mo), they were alive without disease. Histologically, these tumors consisted of well-differentiated rhabdomyoblastic proliferations with nuclear atypia, infiltrative borders, and a specific growth pattern. These tumors harbored new fusion genes involving SRF and either FOXO1 or NCOA1. We compared the expression profiles of these 3 tumors to the expression data of a series of 33 skeletal muscle tumors including embryonal RMSs, alveolar rhandomyosarcomas, RMSs with VGLL2 fusions, RMSs with the myoD1 mutation, EWSR1/FUS-TFCP2 epithelioid and spindle cell RMSs of the bone, and rhabdomyomas with PTCH1 loss. According to clustering analyses, the 3 SRF-fused tumors formed a distinct group with a specific expression profile different from that of the other types of skeletal muscle tumors. Array-comparative genomic hybridization showed a recurrent gain of chromosome 11. These 3 tumors define a new group of RMS associated with a fusion of the SRF gene. FOXO1 rearrangements, usually used to confirm the diagnosis of alveolar RMS and identify poor-outcome RMSs, were identified in a nonalveolar RMS for the first time.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Cell Differentiation
  • Child, Preschool
  • Comparative Genomic Hybridization
  • Female
  • Forkhead Box Protein O1 / genetics*
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • Head and Neck Neoplasms / classification
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / therapy
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • Male
  • Neck Muscles / pathology
  • Nuclear Receptor Coactivator 1 / genetics*
  • Paraspinal Muscles / pathology
  • Phenotype
  • Rhabdomyosarcoma / classification
  • Rhabdomyosarcoma / genetics*
  • Rhabdomyosarcoma / pathology
  • Rhabdomyosarcoma / therapy
  • Sequence Analysis, RNA
  • Serum Response Factor / genetics*
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • SRF protein, human
  • Serum Response Factor
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1