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.
François Le Loarer  #  1  2  3 ,  Arjen H G Cleven  #  4 ,  Corinne Bouvier  5 ,  Marie-Pierre Castex  6 ,  Cleofe Romagosa  7 ,  Anne Moreau  8 ,  Sébastien Salas  9 ,  Benjamin Bonhomme  10 ,  Anne Gomez-Brouchet  11 ,  Camille Laurent  11 ,  Sophie Le Guellec  11 ,  Virginie Audard  12 ,  Antoine Giraud  13 ,  Irma Ramos-Oliver  7 ,  Anne-Marie Cleton-Jansen  4 ,  Dilara C Savci-Heijink  14 ,  Herman M Kroon  15 ,  Jessica Baud  16  17 ,  Daniel Pissaloux  18  19 ,  Gaëlle Pierron  20 ,  Anand Sherwood  21 ,  Jean Michel Coindre  10  16  17 ,  Judith V M G Bovée  4 ,  Frédérique Larousserie  12 ,  Franck Tirode  19
Affiliations
  • 1. Department of Pathology, Institut Bergonié, Bordeaux, France. [email protected].
  • 2. Université de Bordeaux, Talence, France. [email protected].
  • 3. INSERM U1218 ACTION, Institut Bergonie, Bordeaux, France. [email protected].
  • 4. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
  • 5. Department of Pathology, Hôpital La Timone, APHM, Marseille, France.
  • 6. Department of Pediatric Oncology, Oncopôle, Toulouse, France.
  • 7. Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
  • 8. Department of Pathology, CHU Nantes, Nantes, France.
  • 9. Department of Oncology, AP-HM, Marseille, France.
  • 10. Department of Pathology, Institut Bergonié, Bordeaux, France.
  • 11. Department of Pathology, Institut Claudius Regaud-Institut universitaire du cancer-Oncopôle, Toulouse, France.
  • 12. Department of Pathology, Hôpital Cochin, APHP, Paris, France.
  • 13. Department of Clinical Trials, Institut Bergonié, Bordeaux, France.
  • 14. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
  • 15. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
  • 16. Université de Bordeaux, Talence, France.
  • 17. INSERM U1218 ACTION, Institut Bergonie, Bordeaux, France.
  • 18. Department of Biopathologie, Centre Léon Bérard, Lyon, France.
  • 19. Univ Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Cancer Research Center of Lyon, Lyon, France.
  • 20. Department of Biology of Tumors, Institut Curie, Paris, France.
  • 21. Department of Conservative Dentistry and Endodontics, CSI College of Dental Sciences, Madurai, India.
  • # Contributed equally.
PMID: 31383960 DOI: 10.1038/s41379-019-0323-8
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.