| Autor: |
Le Loarer F; Department of Pathology, Institut Bergonié, Bordeaux, France. f.le-loarer@bordeaux.unicancer.fr.; Université de Bordeaux, Talence, France. f.le-loarer@bordeaux.unicancer.fr.; INSERM U1218 ACTION, Institut Bergonie, Bordeaux, France. f.le-loarer@bordeaux.unicancer.fr., Cleven AHG; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Bouvier C; Department of Pathology, Hôpital La Timone, APHM, Marseille, France., Castex MP; Department of Pediatric Oncology, Oncopôle, Toulouse, France., Romagosa C; Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain., Moreau A; Department of Pathology, CHU Nantes, Nantes, France., Salas S; Department of Oncology, AP-HM, Marseille, France., Bonhomme B; Department of Pathology, Institut Bergonié, Bordeaux, France., Gomez-Brouchet A; Department of Pathology, Institut Claudius Regaud-Institut universitaire du cancer-Oncopôle, Toulouse, France., Laurent C; Department of Pathology, Institut Claudius Regaud-Institut universitaire du cancer-Oncopôle, Toulouse, France., Le Guellec S; Department of Pathology, Institut Claudius Regaud-Institut universitaire du cancer-Oncopôle, Toulouse, France., Audard V; Department of Pathology, Hôpital Cochin, APHP, Paris, France., Giraud A; Department of Clinical Trials, Institut Bergonié, Bordeaux, France., Ramos-Oliver I; Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain., Cleton-Jansen AM; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Savci-Heijink DC; Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands., Kroon HM; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands., Baud J; Université de Bordeaux, Talence, France.; INSERM U1218 ACTION, Institut Bergonie, Bordeaux, France., Pissaloux D; Department of Biopathologie, Centre Léon Bérard, Lyon, France.; Univ Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Cancer Research Center of Lyon, Lyon, France., Pierron G; Department of Biology of Tumors, Institut Curie, Paris, France., Sherwood A; Department of Conservative Dentistry and Endodontics, CSI College of Dental Sciences, Madurai, India., Coindre JM; Department of Pathology, Institut Bergonié, Bordeaux, France.; Université de Bordeaux, Talence, France.; INSERM U1218 ACTION, Institut Bergonie, Bordeaux, France., Bovée JVMG; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Larousserie F; Department of Pathology, Hôpital Cochin, APHP, Paris, France., Tirode F; Univ Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Cancer Research Center of Lyon, Lyon, France. |
| Abstrakt: |
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. |
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