NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum

Stevens, Todd M.; Morlote, Diana; Xiu, Joanne; Swensen, Jeffrey; Brandwein‐Weber, Margaret; Miettinen, Markku; Gatalica, Zoran; Bridge, Julia A.

doi:10.1038/s41379-019-0206-z

Cited by 79 publications

(187 citation statements)

References 26 publications

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“…[5][6][7][8]10 Among the initial immunohistochemical workup of our case, CD34 stain was the only positive marker. 6,13 Our case demonstrates that NUTM1rearranged tumors in bone and soft tissue can also show diffuse CD34 expression, which, in the setting of a malignant epithelioid tumor from mesenchymal origin, may lead to the erroneous diagnosis of a malignant epithelioid vascular neoplasm. 5,6,10,13 In the 8 NUTM1rearranged tumors arising in bone, soft tissue, stomach, or intracranial sites that have been tested for CD34, only 2 MGA-NUTM1 fusion tumors show focal CD34 positivity.…”

Section: Discussionmentioning

confidence: 91%

“…13 A subset of conventional NC and soft tissue NUTM1-rearranged tumors has myoepithelial-like morphology, showing hyalinized, myxoid, to chondroid stroma and epithelioid to rhabdoid tumor cells. Despite the morphologic variations in these two cases and our case, ranging from round, epithelioid, to rhabdoid tumor cells, they all share the nuclear features of uniform round to ovoid nuclear contour, vesicular chromatin and prominent nucleoli.…”

Section: Discussionmentioning

confidence: 99%

“…This immunoprofile also supports the previous observation that, unlike typical NC, epithelial and squamous markers, for example, keratins and p63, are only expressed in a minority of NUTM1 cancers arising in bone and soft tissues. 5,6,10,13 In the 8 NUTM1rearranged tumors arising in bone, soft tissue, stomach, or intracranial sites that have been tested for CD34, only 2 MGA-NUTM1 fusion tumors show focal CD34 positivity. CD34 expression has been reported in 55% of typical NC, 25 while the data in NUTM1-rearranged tumors from bone and soft tissue are more limited.…”

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%

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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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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…NCs are typically composed of sheets of predominantly relatively monotonous cuboidal cells with high N/C ratios that show small foci of “abrupt” keratinisation, considered an important morphological “clue” to the diagnosis . However, some NCs appear to completely lack keratinising foci, which is likely absent due to the inherent sampling error of small biopsies. Other morphological variants of NC include gland‐like structures (presumably pseudoglands), small round cells, rhabdoid cells, and chondroid differentiation .…”

Section: Nut Carcinomamentioning

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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A case of metastatic NUT carcinoma with prolonged response on gemcitabine and nab‐paclitaxel

Patel

Singer

Shen

et al. 2021

Clinical Case Reports

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Background NUT carcinoma is an aggressive malignancy characterized by translocations in the NUTM1 gene. There are currently no consensus treatment recommendations for NUT carcinomas. Methods Here, we describe the case of a previously healthy male diagnosed with NUT carcinoma after presenting with sinus pressure, found to have a sinonasal mass and distant metastatic disease in the lungs. While pathologic evaluation and immunohistochemistry were consistent with NUT carcinoma, initial genomic profiling did not demonstrate a NUTM1 translocation. Results Whole transcriptomic RNA sequencing of the tumor revealed a YAP1 ‐ NUTM1 fusion. Based on an in vitro drug sensitivity screen, the patient was treated with gemcitabine and nab‐paclitaxel, achieving a partial response that persisted for 9 months. Conclusions Unbiased transcriptomic sequencing may identify previously uncharacterized NUTM1 fusion partners. Gemcitabine and nab‐paclitaxel is a well‐tolerated combination chemotherapy regimen and could offer a novel treatment approach for NUT carcinoma.

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NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum

Cited by 79 publications

References 26 publications

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

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

Emerging entities in NUTM1‐rearranged neoplasms

A case of metastatic NUT carcinoma with prolonged response on gemcitabine and nab‐paclitaxel

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