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A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma

NUTM1-rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1-rearranged tumors display histologic features of a poorly diff...

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Autores principales: Diolaiti, Daniel, Dela Cruz, Filemon S., Gundem, Gunes, Bouvier, Nancy, Boulad, Mathieu, Zhang, Yanming, Chou, Alexander J., Dunkel, Ira J., Sanghvi, Rashesh, Shah, Minita, Geiger, Heather, Rahman, Sadia, Felice, Vanessa, Wrzeszczynski, Kazimierz O., Darnell, Robert B., Antonescu, Cristina R., French, Christopher A., Papaemmanuil, Elli, Kung, Andrew L., Shukla, Neerav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318763/
https://www.ncbi.nlm.nih.gov/pubmed/30552129
http://dx.doi.org/10.1101/mcs.a003194
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author Diolaiti, Daniel
Dela Cruz, Filemon S.
Gundem, Gunes
Bouvier, Nancy
Boulad, Mathieu
Zhang, Yanming
Chou, Alexander J.
Dunkel, Ira J.
Sanghvi, Rashesh
Shah, Minita
Geiger, Heather
Rahman, Sadia
Felice, Vanessa
Wrzeszczynski, Kazimierz O.
Darnell, Robert B.
Antonescu, Cristina R.
French, Christopher A.
Papaemmanuil, Elli
Kung, Andrew L.
Shukla, Neerav
author_facet Diolaiti, Daniel
Dela Cruz, Filemon S.
Gundem, Gunes
Bouvier, Nancy
Boulad, Mathieu
Zhang, Yanming
Chou, Alexander J.
Dunkel, Ira J.
Sanghvi, Rashesh
Shah, Minita
Geiger, Heather
Rahman, Sadia
Felice, Vanessa
Wrzeszczynski, Kazimierz O.
Darnell, Robert B.
Antonescu, Cristina R.
French, Christopher A.
Papaemmanuil, Elli
Kung, Andrew L.
Shukla, Neerav
author_sort Diolaiti, Daniel
collection PubMed
description NUTM1-rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1-rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the BRD4–NUTM1 fusion gene defining a distinct clinicopathologic entity—NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA–NUTM1 fusion. Whole-genome sequencing identified the presence of complex rearrangements resulting in a MGA–NUTM1 fusion gene in the absence of other significant somatic mutations. Genetic rearrangement was confirmed by fluorescence in situ hybridization, and expression of the fusion gene product was confirmed by transcriptomic analysis. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1–22) and NUTM1 (exons 3–8). Histopathologically, both cases were high-grade spindle cell sarcomas without specific differentiation markers. In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1-rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA–NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high-grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage.
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spelling pubmed-63187632019-01-13 A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma Diolaiti, Daniel Dela Cruz, Filemon S. Gundem, Gunes Bouvier, Nancy Boulad, Mathieu Zhang, Yanming Chou, Alexander J. Dunkel, Ira J. Sanghvi, Rashesh Shah, Minita Geiger, Heather Rahman, Sadia Felice, Vanessa Wrzeszczynski, Kazimierz O. Darnell, Robert B. Antonescu, Cristina R. French, Christopher A. Papaemmanuil, Elli Kung, Andrew L. Shukla, Neerav Cold Spring Harb Mol Case Stud Research Report NUTM1-rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1-rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the BRD4–NUTM1 fusion gene defining a distinct clinicopathologic entity—NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA–NUTM1 fusion. Whole-genome sequencing identified the presence of complex rearrangements resulting in a MGA–NUTM1 fusion gene in the absence of other significant somatic mutations. Genetic rearrangement was confirmed by fluorescence in situ hybridization, and expression of the fusion gene product was confirmed by transcriptomic analysis. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1–22) and NUTM1 (exons 3–8). Histopathologically, both cases were high-grade spindle cell sarcomas without specific differentiation markers. In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1-rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA–NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high-grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage. Cold Spring Harbor Laboratory Press 2018-12 /pmc/articles/PMC6318763/ /pubmed/30552129 http://dx.doi.org/10.1101/mcs.a003194 Text en © 2018 Diolaiti et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Diolaiti, Daniel
Dela Cruz, Filemon S.
Gundem, Gunes
Bouvier, Nancy
Boulad, Mathieu
Zhang, Yanming
Chou, Alexander J.
Dunkel, Ira J.
Sanghvi, Rashesh
Shah, Minita
Geiger, Heather
Rahman, Sadia
Felice, Vanessa
Wrzeszczynski, Kazimierz O.
Darnell, Robert B.
Antonescu, Cristina R.
French, Christopher A.
Papaemmanuil, Elli
Kung, Andrew L.
Shukla, Neerav
A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma
title A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma
title_full A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma
title_fullStr A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma
title_full_unstemmed A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma
title_short A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma
title_sort recurrent novel mga–nutm1 fusion identifies a new subtype of high-grade spindle cell sarcoma
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318763/
https://www.ncbi.nlm.nih.gov/pubmed/30552129
http://dx.doi.org/10.1101/mcs.a003194
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