Transcriptomic definition of molecular subgroups of small round cell sarcomas

Watson, Sarah; Perrin, Virginie; Guillemot, Delphine; Reynaud, Stéphanie; Coindre, Jean‐Michel; Karanian, Marie; Guinebretière, Jean‐Marc; Fréneaux, Paul; Loarer, François Le; Bouvet, Mégane; Galmiche-Rolland, Louise; Larousserie, Frédérique; Longchampt, Élisabeth; Ranchère-Vince, Dominique; Pierron, Gaëlle; Delattre, Olivier; Tirode, Franck

doi:10.1002/path.5053

Cited by 265 publications

(368 citation statements)

References 38 publications

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“…Very recently, YAP1 – KMT2A fusion transcript was detected in a single unclassifiable sarcoma case in a large molecular series, and our report confirms that this fusion is recurrent in sarcoma. That case (SARC002) affected the chest wall of a 35‐year‐old woman; however, its histomorphology, immunophenotype and clinical course were undescribed.…”

Section: Discussionsupporting

confidence: 85%

KMT2A (MLL) fusions in aggressive sarcomas in young adults

et al. 2019

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Aim To characterise unclassifiable sarcomas by use of a combined histological and molecular approach. Methods and results Using RNA sequencing, we identified in‐frame fusions involving KMT2A (MLL) in two cases. Case 1 was a 20‐year‐old woman with a deep soft tissue mass in the thigh. The tumour consisted of monomorphic round, epithelioid and spindle cells in a highly sclerotic background that were focally immunopositive for CD34, CD31, and ERG. Case 2 was a 30‐year‐old woman with a tumour that affected the femur and surrounding soft tissue. The tumour consisted of monomorphic round to spindle cells that were immunopositive for BCOR, Wilms tumour 1, and NKX2‐2. Both tumours were aggressive and had metastasised to the lung; both patients died within a few years. RNA sequencing identified a YAP1 (exon 5)–KMT2A (exon 4) fusion in case 1 and a VIM (exon 4)–KMT2A (exon 2) fusion in case 2, both of which were confirmed by reverse transcription polymerase chain reaction, Sanger sequencing, and fluorescence in‐situ hybridisation. The fusion protein structure was different from that in acute leukaemia, suggesting a novel oncogenic mechanism. Conclusions KMT2A fusions account for a subset of aggressive unclassifiable sarcomas in young adults. Although it is presently unclear whether these sarcomas belong to a single group, the well‐established role of KMT2A fusions as drivers of acute leukaemia and a recent publication regarding identification of YAP1–KMT2A in one unclassifiable sarcoma support the significance of these fusions. Further studies on additional cases are necessary to fully understand the clinicopathological and molecular aspects of KMT2A‐rearranged sarcomas.

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Section: Discussionsupporting

confidence: 85%

KMT2A (MLL) fusions in aggressive sarcomas in young adults

et al. 2019

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“…[5][6][7][8][9][10][11][12][13] As the relationship between these tumors and conventional NC is still unclear, the classification terminology used in the literature varies, including NUT-associated tumors, 5 malignant epithelioid neoplasia, 7 NUT carcinomas, 11 and sarcomas. [5][6][7][8][9][11][12][13] In this study, we report a primary bone with ZNF592-NUTM1 fusion. [5][6][7][8][9][11][12][13] In this study, we report a primary bone with ZNF592-NUTM1 fusion.…”

Section: Discussionmentioning

confidence: 99%

“…2 With high sensitivity (87%) and specificity (100%), NUT immunostain has been utilized as a diagnostic substitute for molecular testing. [5][6][7][8][9][10][11][12][13] These tumors exhibit a wider and more heterogeneous morphologic spectrum compared to typical NC. 4 Recently, NUTM1 gene rearrangements have been increasingly identified in other cancers.…”

Section: Introductionmentioning

confidence: 99%

Primary malignant epithelioid and rhabdoid tumor of bone harboring ZNF532‐NUTM1 fusion: the expanding NUT cancer family

Chien

Hsieh

Chu

et al. 2019

Genes Chromosomes & Cancer

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NUTM1 gene rearrangement is the genetic hallmark of NUT carcinoma, an aggressive tumor that most commonly affects the thoracic and head and neck regions and often exhibits squamous differentiation. The most common fusion partner gene is BRD4, followed by BRD3 and NSD3. Recently, NUTM1 gene rearrangement has been identified in rare tumors from soft tissues, intracranial locations, and other visceral organs. These tumors often show high grade malignant epithelioid to round cell histomorphology and lack evidence of squamous and/or epithelial differentiation. Therefore, their relationship with classic NUT carcinoma is still uncertain. Here, we present a primary mandible bone tumor of a 21‐year‐old female exhibiting monotonous epithelioid and rhabdoid cytomorphology, vesicular chromatin, and prominent nucleoli. The initial immunohistochemical workup was non‐specific, showing only CD34 positivity while being negative for cytokeratin (AE1/AE3), EMA, p63, etc. INI‐1 expression was retained. RNA sequencing was performed and identified a rare ZNF532‐NUTM1 gene fusion, which had only been reported in a single case of pulmonary NUT carcinoma. The fusion was confirmed by FISH for NUTM1 gene rearrangement and supported by diffuse and strong NUT immunoreactivity. MYC mRNA up‐regulation and immunoreactivity, a common finding in NUT carcinoma, was also observed in this tumor, suggesting a possible common pathogenetic mechanism and potential treatment target. The patient presented with a non‐metastatic disease status and received hemimandibulectomy, selective neck dissection (level Ib), and post‐operative radiation therapy. She remained disease free 3.6 years after the initial diagnosis.

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“…CIC is typically fused to DUX4 or FOXO4 . However, NUTM1 has also recently emerged as a recurrent CIC fusion partner . CIC is a transcriptional repressor that interacts with DNA via a high motility group (HMG) box in conjunction with a C‐terminal C1 domain .…”

Section: Other Nutm1‐associated Solid Tumorsmentioning

confidence: 99%

“…Based on the partial similarity to NCs, Schaefer and colleagues concluded that a case of CIC‐NUTM1 NRN was best considered as a NC rather than a Ewing family tumor . However, others have shown that CIC‐NUTM1 tumors have transcriptome profiles similar to CIC‐DUX4 and CIC‐FOXO4 Ewing family tumors and are distinct from BRD4/3‐NUTM1 NCs . Moreover, their methylome profiles and overall morphology has also been reported to be extremely similar to CIC‐DUX4 and CIC‐FOXO4 tumors .…”

Section: Other Nutm1‐associated Solid Tumorsmentioning

confidence: 99%

Emerging entities in NUTM1‐rearranged neoplasms

McEvoy

Fox

Prall

2020

Genes Chromosomes & Cancer

106

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Structural alterations of NUTM1 were originally thought to be restricted to poorly differentiated carcinomas with variable squamous differentiation originating in the midline organs of children and adolescents. Termed NUT carcinomas (NCs), they were defined by a t(15;19) chromosomal rearrangement that was found to result in a BRD4‐NUTM1 gene fusion. However, the use of DNA and RNA‐based next‐generation sequencing has recently revealed a multitude of new NUTM1 fusion partners in a diverse array of neoplasms including sarcoma‐like tumors, poromas, and acute lymphoblastic leukemias (ALLs) that we propose to call NUTM1‐rearranged neoplasms (NRNs). Intriguingly, the nosology of NRNs often correlates with the functional classification of the fusion partner, suggesting different oncogenic mechanisms within each NRN division. Indeed, whereas NCs are characterized by their aggressiveness and intransigence to standard therapeutic measures, the more positive clinical outcomes seen in some sarcoma and ALL NRNs may reflect these mechanistic differences. Here we provide a broad overview of the molecular, nosological, and clinical features in these newly discovered neoplastic entities. We describe how aberrant expression of NUTM1 due to fusion with an N‐terminal DNA/chromatin‐binding protein can generate a potentially powerful chromatin modifier that can give rise to oncogenic transformation in numerous cellular contexts. We also conclude that classification, clinical behavior, and therapeutic options may be best defined by the NUTM1 fusion partner rather than by tumor morphology or immunohistochemical profile.

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Transcriptomic definition of molecular subgroups of small round cell sarcomas

Cited by 265 publications

References 38 publications

KMT2A (MLL) fusions in aggressive sarcomas in young adults

KMT2A (MLL) fusions in aggressive sarcomas in young adults

Primary malignant epithelioid and rhabdoid tumor of bone harboring ZNF532‐NUTM1 fusion: the expanding NUT cancer family

Emerging entities in NUTM1‐rearranged neoplasms

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