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. GroundlandBryan 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^*

^*Corresponding author for this work

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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 “immune intermediate” cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).

Original language	English
Article number	4206
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-58678-6
State	Published - Dec 2025

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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), Article 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 “immune intermediate” 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",

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

language = "English",

volume = "16",

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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, no. 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).

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