MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes

David J. Papke; John S.A. Chrisinger; Christopher A. French; Anthony Crymes; Thomas C. Krivak; Ricardo E. Estape; Mahesh Seetharam; Reema A. Patel; William N. O'Connor; Anthony W. Chi; Pablo Gutman; Stephan Singer; Chul Kim; David A. Bryant; Matthew J. Oberley; Tolulope Adeyelu; Julia A. Bridge; Mark G. Evans

doi:10.1016/j.modpat.2025.100729

MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes

David J. Papke, John S.A. Chrisinger, Christopher A. French, Anthony Crymes, Thomas C. Krivak, Ricardo E. Estape, Mahesh Seetharam, Reema A. Patel, William N. O'Connor, Anthony W. Chi, Pablo Gutman, Stephan Singer, Chul Kim, David A. Bryant, Matthew J. Oberley, Tolulope Adeyelu, Julia A. Bridge, Mark G. Evans

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

NUT fusion–associated cancers are heterogeneous and include NUT carcinoma and an emerging group with non-BRD4/BRD3/NSD3 fusion partners. In this study, we characterized 11 tumors harboring MAD::NUT fusions (10/11 in female patients; median age: 48 years; range: 1-67 years), all histologically different from NUT carcinoma. Eight cases were identified via sequencing database review and 3 were diagnosed prospectively. Eight (73%) patients presented with multifocal disease, including 6 with disseminated peritoneal tumors; 3 (27%) presented with solitary colonic, pulmonary, or orbital masses. Nine (82%) tumors harbored NUTM1 fusions, with MXI1 (5/9; 56%), MXD4 (2/9; 22%), and MGA (2/9; 22%). One tumor each harbored MXD4::NUTM2G and MXI1::NUTM2A fusions. The 9 MXD4/MXI1-rearranged sarcomas were high-grade, with epithelioid-to-spindle cell cytomorphology, amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Histologic features included infiltrative growth (7/7 assessable tumors), rhabdoid morphology (7/9; 78%), prominent collagen (3/9; 33%), multinucleated tumor cells (2/9; 22%), and myxoid stroma (1/9; 11%). MXD4/MXI1-rearranged sarcomas expressed desmin (3/7; 43%) and keratin(s) (3/7; 43%), and not p63 (6 tumors), CD34 (5 tumors), or S-100 (5 tumors). The adult MGA::NUTM1 fusion sarcoma exhibited some cytologic overlap with MXD4/MXI1-rearranged sarcomas but showed lower grade myxoid spindle cell regions, microcystic spaces, and S-100 expression. The pediatric MGA::NUTM1 fusion sarcoma was low-grade with CD34/S-100 coexpression. Immunohistochemistry demonstrated NUTM1 expression in NUTM1-rearranged sarcomas (5/5), and weak and no expression in NUTM2A- and NUTM2G-rearranged sarcomas, respectively. Gene expression profiling demonstrated sarcomas with MXD4/MXI1::NUTM1/NUTM2A/NUTM2G fusions clustered separately from NUT carcinoma. Follow-up was available for 9 patients (82%; median length: 1.8 years; range: 2 months to 8.2 years). Four of 7 patients with MXD4/MXI1-rearranged sarcomas died of disease (median survival: 1.3 years; range: 5 months to 4.8 years), 1 entered hospice at 2 months, 1 was alive with pericardial masses at 2.8 years, and 1 was alive with no evidence of disease at 8.2 years. The adult with the MGA::NUTM1 fusion sarcoma died of other causes at 4.5 years; the child was alive without disease at 11 months. We conclude that MAD::NUT fusions define a sarcoma class distinct from NUT carcinoma. Among this group, MGA::NUTM1 fusion sarcomas might represent a distinctive subset. NUTM1 immunohistochemistry does not reliably detect NUTM2A/NUTM2G-rearranged sarcomas.

Original language	English
Article number	100729
Journal	Modern Pathology
Volume	38
Issue number	5
DOIs	https://doi.org/10.1016/j.modpat.2025.100729
State	Published - May 2025

Bibliographical note

Publisher Copyright:
© 2025 United States & Canadian Academy of Pathology

Funding

The authors would like to gratefully acknowledge Dr Christopher Fletcher and Dr Jason Hornick (Boston, MA), who graciously provided slides for photography, and Dr Gregory Charville (Stanford, CA), who performed NUTM1 immunohistochemistry on one case. The authors would like to thank Ms Jennifer Wagenfuehr and Mr Jason Davidson (Dallas, TX) for their expert technical assistance in fluorescence in situ hybridization probe preparation and analysis. D.J.P. J.S.A.C. C.A.F. J.A.B. D.A.B. M.J.O. and M.G.E. designed the study, analyzed data, and wrote and edited the manuscript. T.A. analyzed data and edited the manuscript. D.J.P. J.S.A.C. A.C. T.C.K. R.E.E. M.S. R.A.P. W.N.O. A.W.C. P.G. S.S. and C.K. provided clinical data. All authors reviewed and approved of the final manuscript. Not applicable. The authors received no funding for this study. M.G.E. T.A. D.A.B. and M.J.O. disclose a financial association with Caris Life Sciences (full-time employment, travel/speaking expenses, stock/stock options). This study was approved in institutional review at the participating institutions. Patient consent was not required for this study.

Funders	Funder number
Caris Life Sciences

Keywords

MAD::NUT fusion sarcoma
MGA
MXI1
NUTM1
NUTM2A
NUTM2G

ASJC Scopus subject areas

Pathology and Forensic Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.modpat.2025.100729

Cite this

Papke, D. J., Chrisinger, J. S. A., French, C. A., Crymes, A., Krivak, T. C., Estape, R. E., Seetharam, M., Patel, R. A., O'Connor, W. N., Chi, A. W., Gutman, P., Singer, S., Kim, C., Bryant, D. A., Oberley, M. J., Adeyelu, T., Bridge, J. A., & Evans, M. G. (2025). MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes. Modern Pathology, 38(5), Article 100729. https://doi.org/10.1016/j.modpat.2025.100729

@article{1e9b1e6fe31146ea8d8970a0129db082,

title = "MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes",

abstract = "NUT fusion–associated cancers are heterogeneous and include NUT carcinoma and an emerging group with non-BRD4/BRD3/NSD3 fusion partners. In this study, we characterized 11 tumors harboring MAD::NUT fusions (10/11 in female patients; median age: 48 years; range: 1-67 years), all histologically different from NUT carcinoma. Eight cases were identified via sequencing database review and 3 were diagnosed prospectively. Eight (73\%) patients presented with multifocal disease, including 6 with disseminated peritoneal tumors; 3 (27\%) presented with solitary colonic, pulmonary, or orbital masses. Nine (82\%) tumors harbored NUTM1 fusions, with MXI1 (5/9; 56\%), MXD4 (2/9; 22\%), and MGA (2/9; 22\%). One tumor each harbored MXD4::NUTM2G and MXI1::NUTM2A fusions. The 9 MXD4/MXI1-rearranged sarcomas were high-grade, with epithelioid-to-spindle cell cytomorphology, amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Histologic features included infiltrative growth (7/7 assessable tumors), rhabdoid morphology (7/9; 78\%), prominent collagen (3/9; 33\%), multinucleated tumor cells (2/9; 22\%), and myxoid stroma (1/9; 11\%). MXD4/MXI1-rearranged sarcomas expressed desmin (3/7; 43\%) and keratin(s) (3/7; 43\%), and not p63 (6 tumors), CD34 (5 tumors), or S-100 (5 tumors). The adult MGA::NUTM1 fusion sarcoma exhibited some cytologic overlap with MXD4/MXI1-rearranged sarcomas but showed lower grade myxoid spindle cell regions, microcystic spaces, and S-100 expression. The pediatric MGA::NUTM1 fusion sarcoma was low-grade with CD34/S-100 coexpression. Immunohistochemistry demonstrated NUTM1 expression in NUTM1-rearranged sarcomas (5/5), and weak and no expression in NUTM2A- and NUTM2G-rearranged sarcomas, respectively. Gene expression profiling demonstrated sarcomas with MXD4/MXI1::NUTM1/NUTM2A/NUTM2G fusions clustered separately from NUT carcinoma. Follow-up was available for 9 patients (82\%; median length: 1.8 years; range: 2 months to 8.2 years). Four of 7 patients with MXD4/MXI1-rearranged sarcomas died of disease (median survival: 1.3 years; range: 5 months to 4.8 years), 1 entered hospice at 2 months, 1 was alive with pericardial masses at 2.8 years, and 1 was alive with no evidence of disease at 8.2 years. The adult with the MGA::NUTM1 fusion sarcoma died of other causes at 4.5 years; the child was alive without disease at 11 months. We conclude that MAD::NUT fusions define a sarcoma class distinct from NUT carcinoma. Among this group, MGA::NUTM1 fusion sarcomas might represent a distinctive subset. NUTM1 immunohistochemistry does not reliably detect NUTM2A/NUTM2G-rearranged sarcomas.",

keywords = "MAD::NUT fusion sarcoma, MGA, MXI1, NUTM1, NUTM2A, NUTM2G",

author = "Papke, \{David J.\} and Chrisinger, \{John S.A.\} and French, \{Christopher A.\} and Anthony Crymes and Krivak, \{Thomas C.\} and Estape, \{Ricardo E.\} and Mahesh Seetharam and Patel, \{Reema A.\} and O'Connor, \{William N.\} and Chi, \{Anthony W.\} and Pablo Gutman and Stephan Singer and Chul Kim and Bryant, \{David A.\} and Oberley, \{Matthew J.\} and Tolulope Adeyelu and Bridge, \{Julia A.\} and Evans, \{Mark G.\}",

note = "Publisher Copyright: {\textcopyright} 2025 United States \& Canadian Academy of Pathology",

year = "2025",

month = may,

doi = "10.1016/j.modpat.2025.100729",

language = "English",

volume = "38",

number = "5",

}

Papke, DJ, Chrisinger, JSA, French, CA, Crymes, A, Krivak, TC, Estape, RE, Seetharam, M, Patel, RA, O'Connor, WN, Chi, AW, Gutman, P, Singer, S, Kim, C, Bryant, DA, Oberley, MJ, Adeyelu, T, Bridge, JA & Evans, MG 2025, 'MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes', Modern Pathology, vol. 38, no. 5, 100729. https://doi.org/10.1016/j.modpat.2025.100729

TY - JOUR

T1 - MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes

AU - Papke, David J.

AU - Chrisinger, John S.A.

AU - French, Christopher A.

AU - Crymes, Anthony

AU - Krivak, Thomas C.

AU - Estape, Ricardo E.

AU - Seetharam, Mahesh

AU - Patel, Reema A.

AU - O'Connor, William N.

AU - Chi, Anthony W.

AU - Gutman, Pablo

AU - Singer, Stephan

AU - Kim, Chul

AU - Bryant, David A.

AU - Oberley, Matthew J.

AU - Adeyelu, Tolulope

AU - Bridge, Julia A.

AU - Evans, Mark G.

PY - 2025/5

Y1 - 2025/5

N2 - NUT fusion–associated cancers are heterogeneous and include NUT carcinoma and an emerging group with non-BRD4/BRD3/NSD3 fusion partners. In this study, we characterized 11 tumors harboring MAD::NUT fusions (10/11 in female patients; median age: 48 years; range: 1-67 years), all histologically different from NUT carcinoma. Eight cases were identified via sequencing database review and 3 were diagnosed prospectively. Eight (73%) patients presented with multifocal disease, including 6 with disseminated peritoneal tumors; 3 (27%) presented with solitary colonic, pulmonary, or orbital masses. Nine (82%) tumors harbored NUTM1 fusions, with MXI1 (5/9; 56%), MXD4 (2/9; 22%), and MGA (2/9; 22%). One tumor each harbored MXD4::NUTM2G and MXI1::NUTM2A fusions. The 9 MXD4/MXI1-rearranged sarcomas were high-grade, with epithelioid-to-spindle cell cytomorphology, amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Histologic features included infiltrative growth (7/7 assessable tumors), rhabdoid morphology (7/9; 78%), prominent collagen (3/9; 33%), multinucleated tumor cells (2/9; 22%), and myxoid stroma (1/9; 11%). MXD4/MXI1-rearranged sarcomas expressed desmin (3/7; 43%) and keratin(s) (3/7; 43%), and not p63 (6 tumors), CD34 (5 tumors), or S-100 (5 tumors). The adult MGA::NUTM1 fusion sarcoma exhibited some cytologic overlap with MXD4/MXI1-rearranged sarcomas but showed lower grade myxoid spindle cell regions, microcystic spaces, and S-100 expression. The pediatric MGA::NUTM1 fusion sarcoma was low-grade with CD34/S-100 coexpression. Immunohistochemistry demonstrated NUTM1 expression in NUTM1-rearranged sarcomas (5/5), and weak and no expression in NUTM2A- and NUTM2G-rearranged sarcomas, respectively. Gene expression profiling demonstrated sarcomas with MXD4/MXI1::NUTM1/NUTM2A/NUTM2G fusions clustered separately from NUT carcinoma. Follow-up was available for 9 patients (82%; median length: 1.8 years; range: 2 months to 8.2 years). Four of 7 patients with MXD4/MXI1-rearranged sarcomas died of disease (median survival: 1.3 years; range: 5 months to 4.8 years), 1 entered hospice at 2 months, 1 was alive with pericardial masses at 2.8 years, and 1 was alive with no evidence of disease at 8.2 years. The adult with the MGA::NUTM1 fusion sarcoma died of other causes at 4.5 years; the child was alive without disease at 11 months. We conclude that MAD::NUT fusions define a sarcoma class distinct from NUT carcinoma. Among this group, MGA::NUTM1 fusion sarcomas might represent a distinctive subset. NUTM1 immunohistochemistry does not reliably detect NUTM2A/NUTM2G-rearranged sarcomas.

AB - NUT fusion–associated cancers are heterogeneous and include NUT carcinoma and an emerging group with non-BRD4/BRD3/NSD3 fusion partners. In this study, we characterized 11 tumors harboring MAD::NUT fusions (10/11 in female patients; median age: 48 years; range: 1-67 years), all histologically different from NUT carcinoma. Eight cases were identified via sequencing database review and 3 were diagnosed prospectively. Eight (73%) patients presented with multifocal disease, including 6 with disseminated peritoneal tumors; 3 (27%) presented with solitary colonic, pulmonary, or orbital masses. Nine (82%) tumors harbored NUTM1 fusions, with MXI1 (5/9; 56%), MXD4 (2/9; 22%), and MGA (2/9; 22%). One tumor each harbored MXD4::NUTM2G and MXI1::NUTM2A fusions. The 9 MXD4/MXI1-rearranged sarcomas were high-grade, with epithelioid-to-spindle cell cytomorphology, amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Histologic features included infiltrative growth (7/7 assessable tumors), rhabdoid morphology (7/9; 78%), prominent collagen (3/9; 33%), multinucleated tumor cells (2/9; 22%), and myxoid stroma (1/9; 11%). MXD4/MXI1-rearranged sarcomas expressed desmin (3/7; 43%) and keratin(s) (3/7; 43%), and not p63 (6 tumors), CD34 (5 tumors), or S-100 (5 tumors). The adult MGA::NUTM1 fusion sarcoma exhibited some cytologic overlap with MXD4/MXI1-rearranged sarcomas but showed lower grade myxoid spindle cell regions, microcystic spaces, and S-100 expression. The pediatric MGA::NUTM1 fusion sarcoma was low-grade with CD34/S-100 coexpression. Immunohistochemistry demonstrated NUTM1 expression in NUTM1-rearranged sarcomas (5/5), and weak and no expression in NUTM2A- and NUTM2G-rearranged sarcomas, respectively. Gene expression profiling demonstrated sarcomas with MXD4/MXI1::NUTM1/NUTM2A/NUTM2G fusions clustered separately from NUT carcinoma. Follow-up was available for 9 patients (82%; median length: 1.8 years; range: 2 months to 8.2 years). Four of 7 patients with MXD4/MXI1-rearranged sarcomas died of disease (median survival: 1.3 years; range: 5 months to 4.8 years), 1 entered hospice at 2 months, 1 was alive with pericardial masses at 2.8 years, and 1 was alive with no evidence of disease at 8.2 years. The adult with the MGA::NUTM1 fusion sarcoma died of other causes at 4.5 years; the child was alive without disease at 11 months. We conclude that MAD::NUT fusions define a sarcoma class distinct from NUT carcinoma. Among this group, MGA::NUTM1 fusion sarcomas might represent a distinctive subset. NUTM1 immunohistochemistry does not reliably detect NUTM2A/NUTM2G-rearranged sarcomas.

KW - MAD::NUT fusion sarcoma

KW - MGA

KW - MXI1

KW - NUTM1

KW - NUTM2A

KW - NUTM2G

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DO - 10.1016/j.modpat.2025.100729

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C2 - 39921028

AN - SCOPUS:85218989292

SN - 0893-3952

VL - 38

JO - Modern Pathology

JF - Modern Pathology

IS - 5

M1 - 100729

ER -

MAD::NUT Fusion Sarcoma: A Sarcoma Class With NUTM1, NUTM2A, and NUTM2G Fusions and Possibly Distinctive Subtypes

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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