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

Loarer, François Le; Cleven, Arjen H.G.; Bouvier, Corinne; Castex, Marie Pierre; Romagosa, Cleofé; Moreau, Anne; Salas, Sébastien; Bonhomme, Benjamin; Gomez‐Brouchet, Anne; Laurent, Camille; Guellec, Sophie Le; Audard, Vincent; 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 Michél; Bovée, Judith V.M.G.; Larousserie, Frédérique; Tirode, Franck

doi:10.1038/s41379-019-0323-8

Cited by 90 publications

(191 citation statements)

References 33 publications

Supporting

Mentioning

176

Contrasting

Unclassified

Order By: Relevance

“…One case with ALK protein expression was negative for rearrangement by FISH and RNA sequencing, which may be explained by false‐positive IHC, gene fusion not covered by the Illumina panel, or genetic alteration other than rearrangement 11 . Secondary ALK expression has recently been reported in diverse entities carrying non‐ ALK gene fusions, including angiomatoid fibrous histiocytoma ( EWSR1 ‐rearranged), 46 rhabdomyosarcoma ( TFCP2 and other rearrangements) 47 and others. This indicates the need for verification of the exact fusion partners in patients selected for novel therapeutic options targeting ALK .…”

Section: Discussionmentioning

confidence: 99%

TERT promoter mutation analysis as a surrogate to morphology and immunohistochemistry in problematic spindle cell lesions of the urinary bladder

et al. 2020

View full text Add to dashboard Cite

TERT promoter mutation analysis as a surrogate to morphology and immunohistochemistry in problematic spindle cell lesions of the urinary bladder Aims: Pseudosarcomatous myofibroblastic proliferations (PSMPs) of the urinary bladder are diagnostically challenging. Diagnostic difficulties are mainly due to frequent cytokeratin expression, variable ALK expression and worrisome morphological features suggestive of malignancy. Conversely, sarcomatoid urothelial carcinoma (UC) may show bland inflammatory myofibroblastic tumour (IMT)-like morphology. TERT promoter mutations are characteristic events in urothelial cancers, but have not been studied in PSMPs. Methods and results: We compared histomorphological and immunohistochemical features and TERT promoter status in 16 PSMPs and 18 sarcomatoid UC. In a subset of PSMPs, RNA sequencing was performed. At least focal IMT-like morphology was seen in nine of 17 sarcomatoid UC. Atypical mitoses, differentiated urothelial component and heterologous elements were the most reliable distinguishing histomorphological features of sarcomatoid UC, if present. A panel of immunohistochemistry (IHC) including ALK (clone D5F3), p53 pattern, p63 and GATA3 reliably distinguished PSMP from sarcomatoid UC. GATA3 (P = 0.001) and p53 patterns (mutant versus wildtype; P < 0.001) were differentially expressed between PSMPs and sarcomatoid UC. Diffuse pancytokeratin staining was significantly associated with PSMPs (10 of 13) compared to four of 14 sarcomatoid UCs (P = 0.012). TERT promoter mutations were found in 17 of 18 sarcomatoid UC versus none of 16 PSMPs (P < 0.001). RNA sequencing revealed ALK genetic rearrangements in one of two ALK-positive and one of 10 ALK-negative PSMPs, which revealed a novel FN1/RET gene fusion. Conclusion: Careful histomorphological analysis and differential IHC reliably distinguish the majority of PSMPs and sarcomatoid UC. In equivocal cases, TERT promoter mutation analysis and/or detection of ALK expression/rearrangements are valuable additional diagnostic adjuncts, strongly supporting sarcomatoid UC and PSMP, respectively.

show abstract

Section: Discussionmentioning

confidence: 99%

TERT promoter mutation analysis as a surrogate to morphology and immunohistochemistry in problematic spindle cell lesions of the urinary bladder

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Other fusion genes involving SRF were identified in soft tissue tumors displaying muscle differentiation: SRF-RELA has been reported in atypical myopericytic tumors (9) and SRF-E2F1 in myoepithelial tumors (22). SRF, located on 6p21, encodes a MADS box family transcriptional factor which regulates, through binding to the CArG box motif, genes involved in cell growth, migration, cytoskeletal organization, and myogenesis (23).…”

Section: Discussionmentioning

confidence: 99%

“…RMSs with MYOD1 mutations occur in children and in adults and have a poor outcome (8). A novel type of translocation-related RMS was also recently reported: intra osseous RMS with a EWSR1-or FUS-TFCP2 (4,9) and MEIS1-NCOA2 fusion gene (10). Finally, a new group of borderline skeletal muscle tumors termed "histiocyte-rich rhabdomyoblastic tumor" was identified, the authors adding a new category of intermediate malignancy to the group of skeletal muscle tumors (11).…”

Section: Introductionmentioning

confidence: 90%

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

Karanian

Pissaloux

Gomez‐Brouchet³

et al. 2020

American Journal of Surgical Pathology

Self Cite

View full text Add to dashboard Cite

Rhabdomyosarcoma encompasses a heterogeneous collection of tumors in which new groups have recently been identified that improved the WHO classification. While performing RNAsequencing in our routine practice, we identified three cases of welldifferentiated rhabdomyosarcoma harboring new fusion genes. We also analyzed these tumors through array-CGH. 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 12-108 months) 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 three tumors to the expression data of a series of 33 skeletal muscle tumors including embryonal rhabdomyosarcomas, alveolar rhandomyosarcomas, rhabdomyosarcomas with VGLL2 fusions, rhabdomyosarcomas with myoD1 mutation, EWSR1/FUS-TFCP2 epithelioid and spindle cell rhabdomyosarcomas of the bone and rhabdomyomas with PTCH1 loss. According to clustering analyses, the three SRF-fused tumors formed a distinct group with a specific expression profile different from that of the other types of skeletal muscle tumors. Array CGH showed a recurrent gain of chromosome 11. These three tumors define a new group of rhabdomyosarcoma associated with a fusion of the SRF gene. FOXO1 rearrangements, usually used to confirm the diagnosis of alveolar rhabdomyosarcoma and identify poor outcome rhabdomyosarcomas, were identified in a non-alveolar rhabdomyosarcoma for the first time.

show abstract

“…The average age is in the third decade. Males and females are affected (almost) equally with a slight female preponderance [172].…”

Section: Epithelioid and Spindle Cell Rhabdomyosarcoma With Ewsr1/fus-tfcp2 Fusionmentioning

confidence: 99%

EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

et al. 2021

View full text Add to dashboard Cite

EWSR1 belongs to the FET family of RNA-binding proteins including also Fused in Sarcoma (FUS), and TATA-box binding protein Associated Factor 15 (TAF15). As consequence of the multifunctional role of EWSR1 leading to a high frequency of transcription of the chromosomal region where the gene is located, EWSR1 is exposed to aberrations such as rearrangements. Consecutive binding to other genes leads to chimeric proteins inducing oncogenesis. The other TET family members are homologous. With the advent of widely used modern molecular techniques during the last decades, it has become obvious that EWSR1 is involved in the development of diverse benign and malignant tumors with mesenchymal, neuroectodermal, and epithelial/myoepithelial features. As oncogenic transformation mediated by EWSR1-fusion proteins leads to such diverse tumor types, there must be a selection on the multipotent stem cell level. In this review, we will focus on the wide variety of soft tissue and bone entities, including benign and malignant lesions, harboring EWSR1 rearrangement. Fusion gene analysis is the diagnostic gold standard in most of these tumors. We present clinicopathologic, immunohistochemical, and molecular features and discuss differential diagnoses.

show abstract

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

Cited by 90 publications

References 33 publications

TERT promoter mutation analysis as a surrogate to morphology and immunohistochemistry in problematic spindle cell lesions of the urinary bladder

TERT promoter mutation analysis as a surrogate to morphology and immunohistochemistry in problematic spindle cell lesions of the urinary bladder

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

EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

Contact Info

Product

Resources

About