Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas
Open accessAbstract
Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.
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MFS, UPS, and DDLS share genomic alterations that result in PI3K/Akt/mTOR and MAPK pathway activation.
“Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [9]
The Conclusions (page unavailable) distinguish the sarcoma types rather than reporting shared PI3K/Akt/mTOR and MAPK activation: they associate AKT/MTOR pathway activation with LMS, Hippo pathway activation with UPS/MFS, and a different set of amplifications with DDLPS. The Results and Discussion section likewise describes aberrant PI3K-AKT-MTOR signaling in LMS, not across the three sarcomas named in the claim. (LLM, conf=0.86)
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Experimental — accuracy not yet measuredIn DDLS, UPS, and MFS, the Hippo pathway is frequently deregulated through increased expression of the transcriptional coactivators YAP and TAZ.
“In DDLS, UPS, and MFS, the Hippo pathway is frequently deregulated through increased expression of the transcriptional coactivators YAP and TAZ (9, 23–25).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [9]
In Results and Discussion (page not provided), the paper reports YAP1 copy-number gains correlated with mRNA expression in DDLPS and UPS/MFS, and a strongly expressed Hippo-pathway YAP1/VGLL3 target signature in UPS/MFS. It does not report increased TAZ expression; it describes possible Hippo-pathway involvement in a subset of UPS/MFS rather than frequent deregulation through increased expression of both YAP and TAZ across all three sarcoma types. (LLM, conf=0.88)
Experimental — accuracy not yet measuredYAP and TAZ are paralogs that share similar functions and oncogenic activation in multiple tumor types, including breast and liver cancer and various soft tissue sarcomas including DDLS, MFS, and UPS.
“The Hippo effectors YAP and TAZ are paralogs that share similar functions and oncogenic activation in multiple tumor types, including breast and liver cancer and various soft tissue sarcomas including DDLS, MFS, and UPS (9, 23, 24).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [9]
The Results and Discussion report YAP1 amplification in a subset of DDLPS and UPS/MFS tumors, and suggest that a subset of UPS/MFS may be driven by Hippo signaling. The passages do not establish that YAP and TAZ are paralogs with similar functions, or address their oncogenic activation in breast or liver cancer. The sarcoma findings concern YAP1, not TAZ. (LLM, conf=0.88)
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Flagged first, then by citations
Research works printed but not linked: 2
- Burgess M Bolejack V Van T BA Schuetze S Hu J D'Angelo S Attia S Riedel R Priebat D Movva S 2017 Pembrolizumab in advanced soft tissue and bone sarcomas: results of SARC028, a multicentre, single arm, phase 2 trial Lancet Oncol in press PMC7939029 28988646
- Fletcher CDM Bridge J Hogendoorn PCW Mertens F 2013 WHO Classification of Tumours of Soft Tissue and Bone Geneva WHO Press
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- Authors
- Abeshouse, A., Adebamowo, C., Adebamowo, S. N., Akbani, R., Akeredolu, T., Ally, A., Anderson, M. L., Anur, P., Appelbaum, E. L., Armenia, J., Auman, J. T., Bailey, M. H., Baker, L., Balasundaram, M., Balu, S., Barthel, F. P., Bartlett, J., Baylin, S. B., Behera, M., Belyaev, D., Bennett, J., Benz, C., Beroukhim, R., Birrer, M., Bocklage, T., Bodenheimer, T., Boice, L., Bootwalla, M. S., Bowen, J., Bowlby, R., Boyd, J., Brohl, A. S., Brooks, D., Byers, L., Carlsen, R., Castro, P., Chen, H.-W., Cherniack, A. D., Chibon, F., Chin, L., Cho, J., Chuah, E., Chudamani, S., Cibulskis, C., Cooper, L. A. D., Cope, L., Cordes, M. G., Crain, D., Curley, E., Danilova, L., Dao, F., Davis, I. J., Davis, L. E., Defreitas, T., Delman, K., Demchok, J. A., Demetri, G. D., Demicco, E. G., Dhalla, N., Diao, L., Ding, L., DiSaia, P., Dottino, P., Doyle, L. A., Drill, E., Dubina, M., Eschbacher, J., Fedosenko, K., Felau, I., Ferguson, M. L., Frazer, S., Fronick, C. C., Fulidou, V., Fulton, L. A., Fulton, R. S., Gabriel, S. B., Gao, J., Gao, Q., Gardner, J., Gastier-Foster, J. M., Gay, C. M., Gehlenborg, N., Gerken, M., Getz, G., Godwin, A. K., Godwin, E. M., Gordienko, E., Grilley-Olson, J. E., Gutman, D. A., Gutmann, D. H., Hayes, D. N., Hegde, A. M., Heiman, D. I., Heins, Z., Helsel, C., Hepperla, A. J., Higgins, K., Hoadley, K. A., Hobensack, S., Holt, R. A., Hoon, D. B., Hornick, J. L., Hoyle, A. P., Hu, X., Huang, M., Hutter, C. M., Iacocca, M., Ingram, D. R., Ittmann, M., Iype, L., Jefferys, S. R., Jones, K. B., Jones, C. D., Jones, S. J. M., Kalir, T., Karlan, B. Y., Karseladze, A., Kasaian, K., Kim, J., Kundra, R., Kuo, H., Ladanyi, M., Lai, P. H., Laird, P. W., Larsson, E., Lawrence, M. S., Lazar, A. J., Lee, S., Lee, D., Lehmann, K.-V., Leraas, K. M., Lester, J., Levine, D. A., Li, I., Lichtenberg, T. M., Lin, P., Liu, J., Liu, W., Liu, E. M., Lolla, L., Lu, Y., Ma, Y., Madan, R., Maglinte, D. T., Magliocco, A., Maki, R. G., Mallery, D., Manikhas, G., Mardis, E. R., Mariamidze, A., Marra, M. A., Martignetti, J. A., Martinez, C., Mayo, M., McLellan, M. D., Meier, S., Meng, S., Meyerson, M., Mieczkowski, P. A., Miller, C. A., Mills, G. B., Moore, R. A., Morris, S., Mose, L. E., Mozgovoy, E., Mungall, A. J., Mungall, K., Nalisnik, M., Naresh, R., Newton, Y., Noble, M. S., Novak, J. E., Ochoa, A., Olvera, N., Owonikoko, T. K., Paklina, O., Parfitt, J., Parker, J. S., Pastore, A., Paulauskis, J., Penny, R., Pereira, E., Perou, C. M., Perou, A. H., Pihl, T., Pollock, R. E., Potapova, O., Radenbaugh, A. J., Ramalingam, S. S., Ramirez, N. C., Rathmell, W. K., Raut, C. P., Riedel, R. F., Reilly, C., Reynolds, S. M., Roach, J., Robertson, A. G., Roszik, J., Rubin, B. P., Sadeghi, S., Saksena, G., Salner, A., Sanchez-Vega, F., Sander, C., Schein, J. E., Schmidt, H. K., Schultz, N., Schumacher, S. E., Sekhon, H., Senbabaoglu, Y., Setdikova, G., Shelton, C., Shelton, T., Shen, R., Shi, Y., Shih, J., Shmulevich, I., Sica, G. L., Simons, J. V., Singer, S., Sipahimalani, P., Skelly, T., Socci, N., Sofia, H. J., Soloway, M. G., Spellman, P., Sun, Q., Swanson, P., Tam, A., Tan, D., Tarnuzzer, R., Thiessen, N., Thompson, E., Thorne, L. B., Tong, P., Torres, K. E., van de Rijn, M., Van Den Berg, D. J., Van Tine, B. A., Veluvolu, U., Verhaak, R., Voet, D., Voronina, O., Wan, Y., Wang, Z., Wang, J., Weinstein, J. N., Weisenberger, D. J., Wilkerson, M. D., Wilson, R. K., Wise, L., Wong, T., Wong, W., Wrangle, J., Wu, Y., Wyczalkowski, M., Yang, L., Yau, C., Yellapantula, V., Zenklusen, J. C., Zhang, J. (., Zhang, H., Zhang, H., & Zmuda, E.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Adebamowo, Clement
- Adebamowo, Sally N.
- Auman, J. Todd
- Barthel, Floris P.
- Bartlett, John
- Beroukhim, Rameen
- Brohl, Andrew S.
- Cherniack, Andrew D.
- Cibulskis, Carrie
- Davis, Ian J.
- Demicco, Elizabeth G.
- Fulton, Lucinda A.
- Gabriel, Stacey B.
- Getz, Gad
- Gutmann, David H.
- Heiman, David I.
- Heins, Zachary
- Hepperla, Austin J.
- Hoadley, Katherine A.
- Holt, Robert A.
- Jones, Kevin B.
- Karlan, Beth Y.
- Kim, Jaegil
- Kundra, Ritika
- Laird, Peter W.
- Lawrence, Michael S.
- Lehmann, Kjong-Van
- Maki, Robert G.
- Mariamidze, Armaz
- Marra, Marco A.
- McLellan, Michael D.
- Meyerson, Matthew
- Mieczkowski, Piotr A.
- Mozgovoy, Evgeny
- Mungall, Andrew J.
- Noble, Michael S.
- Perou, Charles M.
- Pollock, Raphael E.
- Rathmell, W. Kimryn
- Riedel, Richard F.
- Roszik, Jason
- Saksena, Gordon
- Sander, Chris
- Schumacher, Steven E.
- Setdikova, Galiya
- Sica, Gabriel L.
- Singer, Samuel
- Socci, Nicholas
- Spellman, Paul
- Tam, Angela
- Tarnuzzer, Roy
- Verhaak, Roel
- Wang, Jing
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 171
- Issue
- 4
- Pages
- 950-965.e28
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5693358
- OpenAlex
- W2765468373
- Cited by
- 1,069
- References
- 87
- Citations by year
- 2026: 80 · 2025: 113 · 2024: 127 · 2023: 146 · 2022: 143 · 2021: 146 · 2020: 132 · 2019: 102 · 2018: 74 · 2017: 3
- FWCI
- 70.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, U24 CA211006, P30 CA016672)
- Bayer AG
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- adult soft tissue sarcoma, copy number alterations, somatic mutations, TP53, ATRX, RB1, molecular subtypes, DNA methylation, tumor immune microenvironment, immune checkpoint inhibitors, patient outcomes
- MeSH terms
- Adult, Aged, Aged, 80 and over, Humans, Middle Aged, Mutation, Sarcoma, Genome, Human, Cluster Analysis, Genome-Wide Association Study, Young Adult, DNA Copy Number Variations, Epigenomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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