Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes

Alex Soupir; Oscar E. Ospina; Oliver Hampton; Michelle Churchman; Michael Radmacher; Dale Hedges; David McKean; Phaedra Agius; Saman Zeeshan; Nathan D. Seligson; Raphael Pollock; David Liebner; James L. Chen; Gabriel Tinoco; Bodour Salhia; Martin McCarter; Breelyn A. Wilky; Benjamin J. Miller; Michael J. Cavnar; John S. Groundland; Bryan P. Schneider; Gregory Riedlinger; Stephen B. Edge; Christopher A. Moskaluk; Kenneth Cardona; Abdul Rafeh Naqash; Ricardo J. Gonzalez; John E. Mullinax; David M. Joyce; Odion Binitie; G. Douglas Letson; Arash O. Naghavi; Mihaela Druta; Damon R. Reed; Erin M. Siegel; Jamie K. Teer; Brooke L. Fridley; Andrew S. Brohl

doi:10.1038/s41467-025-58678-6

Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes

Alex Soupir
, Oscar E. Ospina
, Oliver Hampton
, Michelle Churchman
, Michael Radmacher
, Dale Hedges
, David McKean
, Phaedra Agius
, Saman Zeeshan
, Nathan D. Seligson
, Raphael Pollock
, David Liebner
, James L. Chen
, Gabriel Tinoco
, Bodour Salhia
, Martin McCarter
, Breelyn A. Wilky
, Benjamin J. Miller
, Michael J. Cavnar
, John S. Groundland

Bryan P. Schneider, Gregory Riedlinger, Stephen B. Edge, Christopher A. Moskaluk, Kenneth Cardona, Abdul Rafeh Naqash, Ricardo J. Gonzalez, John E. Mullinax, David M. Joyce, Odion Binitie, G. Douglas Letson, Arash O. Naghavi, Mihaela Druta, Damon R. Reed, Erin M. Siegel, Jamie K. Teer, Brooke L. Fridley, Andrew S. Brohl

Producción científica: Article › revisión exhaustiva

12 Citas (Scopus)

Resumen

Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p < 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p < 0.01). Interestingly, GIST predominantly form a distinct “immune intermediate” cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).

Idioma original	English
Número de artículo	4206
Publicación	Nature Communications
Volumen	16
N.º	1
DOI	https://doi.org/10.1038/s41467-025-58678-6
Estado	Published - dic 2025

Nota bibliográfica

Publisher Copyright:
© The Author(s) 2025.

Financiación

Funding for publication of this work was supported by the AmandaLee Sarcoma Fund, Moffitt Cancer Center. O.H., M.C., M.R., D.H., D.M., P.A. and S.Z. are or were employed by Aster Insights. E.S. received research funding from the ORIEN Foundation. D.L. – advisory board with Aadi Biosciences and patent licensing (US 10,65,347 B2: Method for Predicting Prognosis) with MatchTx, Inc. J.L.C. is an employee of Tempus. G.T. - advisory board with SynOx, Deciphera, Daiichi Sankyo. B.A.W. – consulting or advisory role with Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, research funding from Exelixis, and travel expenses from Agenus. G.R. – advisory board with AstraZeneca. A.R.N. – advisory board with Foundation Medicine and NGM biosciences, travel compensation from Foundation Medicine and Caris Life Sciences, D.R.R. – data safety monitoring committee for Eisai and Springworks. M.D. – consulting AdaptImuune, Deciphera, and Aaid Biosciences. A.S.B – advisory board with Deciphera, research funding (institution) from Merck. The remaining authors declare no competing interests.

Financiadores
AmandaLee Sarcoma Fund
Moffitt Cancer Center’s Cancer Center
ORIEN Foundation

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-025-58678-6

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Soupir, A., Ospina, O. E., Hampton, O., Churchman, M., Radmacher, M., Hedges, D., McKean, D., Agius, P., Zeeshan, S., Seligson, N. D., Pollock, R., Liebner, D., Chen, J. L., Tinoco, G., Salhia, B., McCarter, M., Wilky, B. A., Miller, B. J., Cavnar, M. J., ... Brohl, A. S. (2025). Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes. Nature Communications, 16(1), Artículo 4206. https://doi.org/10.1038/s41467-025-58678-6

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title = "Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes",

abstract = "Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p < 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p < 0.01). Interestingly, GIST predominantly form a distinct {\textquotedblleft}immune intermediate{\textquotedblright} cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).",

author = "Alex Soupir and Ospina, \{Oscar E.\} and Oliver Hampton and Michelle Churchman and Michael Radmacher and Dale Hedges and David McKean and Phaedra Agius and Saman Zeeshan and Seligson, \{Nathan D.\} and Raphael Pollock and David Liebner and Chen, \{James L.\} and Gabriel Tinoco and Bodour Salhia and Martin McCarter and Wilky, \{Breelyn A.\} and Miller, \{Benjamin J.\} and Cavnar, \{Michael J.\} and Groundland, \{John S.\} and Schneider, \{Bryan P.\} and Gregory Riedlinger and Edge, \{Stephen B.\} and Moskaluk, \{Christopher A.\} and Kenneth Cardona and Naqash, \{Abdul Rafeh\} and Gonzalez, \{Ricardo J.\} and Mullinax, \{John E.\} and Joyce, \{David M.\} and Odion Binitie and \{Douglas Letson\}, G. and Naghavi, \{Arash O.\} and Mihaela Druta and Reed, \{Damon R.\} and Siegel, \{Erin M.\} and Teer, \{Jamie K.\} and Fridley, \{Brooke L.\} and Brohl, \{Andrew S.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-58678-6",

language = "English",

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Soupir, A, Ospina, OE, Hampton, O, Churchman, M, Radmacher, M, Hedges, D, McKean, D, Agius, P, Zeeshan, S, Seligson, ND, Pollock, R, Liebner, D, Chen, JL, Tinoco, G, Salhia, B, McCarter, M, Wilky, BA, Miller, BJ, Cavnar, MJ, Groundland, JS, Schneider, BP, Riedlinger, G, Edge, SB, Moskaluk, CA, Cardona, K, Naqash, AR, Gonzalez, RJ, Mullinax, JE, Joyce, DM, Binitie, O, Douglas Letson, G, Naghavi, AO, Druta, M, Reed, DR, Siegel, EM, Teer, JK, Fridley, BL & Brohl, AS 2025, 'Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes', Nature Communications, vol. 16, n.º 1, 4206. https://doi.org/10.1038/s41467-025-58678-6

TY - JOUR

T1 - Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes

AU - Soupir, Alex

AU - Ospina, Oscar E.

AU - Hampton, Oliver

AU - Churchman, Michelle

AU - Radmacher, Michael

AU - Hedges, Dale

AU - McKean, David

AU - Agius, Phaedra

AU - Zeeshan, Saman

AU - Seligson, Nathan D.

AU - Pollock, Raphael

AU - Liebner, David

AU - Chen, James L.

AU - Tinoco, Gabriel

AU - Salhia, Bodour

AU - McCarter, Martin

AU - Wilky, Breelyn A.

AU - Miller, Benjamin J.

AU - Cavnar, Michael J.

AU - Groundland, John S.

AU - Schneider, Bryan P.

AU - Riedlinger, Gregory

AU - Edge, Stephen B.

AU - Moskaluk, Christopher A.

AU - Cardona, Kenneth

AU - Naqash, Abdul Rafeh

AU - Gonzalez, Ricardo J.

AU - Mullinax, John E.

AU - Joyce, David M.

AU - Binitie, Odion

AU - Douglas Letson, G.

AU - Naghavi, Arash O.

AU - Druta, Mihaela

AU - Reed, Damon R.

AU - Siegel, Erin M.

AU - Teer, Jamie K.

AU - Fridley, Brooke L.

AU - Brohl, Andrew S.

PY - 2025/12

Y1 - 2025/12

N2 - Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p < 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p < 0.01). Interestingly, GIST predominantly form a distinct “immune intermediate” cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).

AB - Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p < 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p < 0.01). Interestingly, GIST predominantly form a distinct “immune intermediate” cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).

UR - https://www.scopus.com/pages/publications/105004779385

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U2 - 10.1038/s41467-025-58678-6

DO - 10.1038/s41467-025-58678-6

M3 - Article

C2 - 40328759

AN - SCOPUS:105004779385

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4206

ER -

Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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