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

• Published in: Modern pathology 2020-03, Vol.33 (3), p.404-419
• Main Authors: Le Loarer, François, Cleven, Arjen H. G., Bouvier, Corinne, Castex, Marie-Pierre, Romagosa, Cleofe, Moreau, Anne, Salas, Sébastien, Bonhomme, Benjamin, Gomez-Brouchet, Anne, Laurent, Camille, Le Guellec, Sophie, Audard, Virginie, Giraud, Antoine, Ramos-Oliver, Irma, Cleton-Jansen, Anne-Marie, Savci-Heijink, Dilara C., Kroon, Herman M., Baud, Jessica, Pissaloux, Daniel, Pierron, Gaëlle, Sherwood, Anand, Coindre, Jean Michel, Bovée, Judith V. M. G., Larousserie, Frédérique, Tirode, Franck
• Format: Article
• Language: English
• Subjects: 14/32; 38/91; 45/61; 45/77; 631/337/2019; 631/67/1798; 631/67/69; 692/308/575; 82/51; Adolescent; Adult; Aged, 80 and over; Anaplastic Lymphoma Kinase - genetics; Biochemistry, Molecular Biology; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Bone tumors; Bones; Cancer; Child; Clonal deletion; DNA-Binding Proteins - genetics; Epithelioid Cells - pathology; Female; FLI-1 protein; Fluorescence in situ hybridization; Gene Fusion; Genetic Predisposition to Disease; Genomics; Humans; Immunohistochemistry; Laboratory Medicine; Life Sciences; Male; Medicine; Medicine & Public Health; Middle Aged; Molecular biology; Molecular Diagnostic Techniques; Next-generation sequencing; Pathology; Phenotype; Phenotypes; Prognosis; Prospective Studies; Retrospective Studies; Rhabdomyosarcoma; Rhabdomyosarcoma - chemistry; Rhabdomyosarcoma - genetics; Rhabdomyosarcoma - mortality; Rhabdomyosarcoma - pathology; Ribonucleic acid; RNA; Sarcoma; Transcription; Transcription Factors - genetics; Up-Regulation; Young Adult
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-019-0323-8

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.