The Molecular Biology of Soft Tissue Sarcomas: Current Knowledge and Future Perspectives
Abstract
:Simple Summary
Abstract
1. Introduction
2. Molecular Biology for Sarcoma Diagnosis
3. Sarcomas with “Simple Genetics”
3.1. Gene Fusions
3.2. Mutations
3.2.1. Activating Mutations
3.2.2. Inactivating Mutations
3.3. Gene Amplifications
4. Sarcomas with “Complex Genetics”
5. Molecular Biology for Sarcoma Treatment
5.1. Gene Fusions
5.2. Mutations
5.3. Gene Amplifications
6. Perspectives
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Kallen, M.E.; Hornick, J.L. The 2020 WHO Classification: What’s New in Soft Tissue Tumor Pathology? Am. J. Surg. Pathol. 2021, 45, e1–e23. [Google Scholar] [CrossRef] [PubMed]
- Dufresne, A.; Brahmi, M.; Karanian, M.; Blay, J.-Y. Using Biology to Guide the Treatment of Sarcomas and Aggressive Connective-Tissue Tumours. Nat. Rev. Clin. Oncol. 2018, 15, 443–458. [Google Scholar] [CrossRef] [PubMed]
- Taylor, B.S.; Barretina, J.; Maki, R.G.; Antonescu, C.R.; Singer, S.; Ladanyi, M. Advances in Sarcoma Genomics and New Therapeutic Targets. Nat. Rev. Cancer 2011, 11, 541–557. [Google Scholar] [CrossRef] [Green Version]
- Abeshouse, A.; Adebamowo, C.; Adebamowo, S.N.; Akbani, R.; Akeredolu, T.; Ally, A.; Anderson, M.L.; Anur, P.; Appelbaum, E.L.; Armenia, J.; et al. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. Cell 2017, 171, 950–965.e28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mertens, F.; Antonescu, C.R.; Hohenberger, P.; Ladanyi, M.; Modena, P.; D’Incalci, M.; Casali, P.G.; Aglietta, M.; Alvegård, T. Translocation-Related Sarcomas. Semin. Oncol. 2009, 36, 312–323. [Google Scholar] [CrossRef] [PubMed]
- Riggi, N.; Suvà, M.L.; Stamenkovic, I. Ewing’s Sarcoma. N. Engl. J. Med. 2021, 384, 154–164. [Google Scholar] [CrossRef]
- Delattre, O.; Zucman, J.; Plougastel, B.; Desmaze, C.; Melot, T.; Peter, M.; Kovar, H.; Joubert, I.; de Jong, P.; Rouleau, G.; et al. Gene Fusion with an ETS DNA-Binding Domain Caused by Chromosome Translocation in Human Tumours. Nature 1992, 359, 162–165. [Google Scholar] [CrossRef]
- Schaefer, I.-M.; Cote, G.M.; Hornick, J.L. Contemporary Sarcoma Diagnosis, Genetics, and Genomics. J. Clin. Oncol. 2018, 36, 101–110. [Google Scholar] [CrossRef]
- Watson, S.; Perrin, V.; Guillemot, D.; Reynaud, S.; Coindre, J.-M.; Karanian, M.; Guinebretière, J.-M.; Freneaux, P.; Loarer, F.L.; Bouvet, M.; et al. Transcriptomic Definition of Molecular Subgroups of Small Round Cell Sarcomas. J. Pathol. 2018, 245, 29–40. [Google Scholar] [CrossRef] [Green Version]
- Macagno, N.; Pissaloux, D.; de la Fouchardière, A.; Karanian, M.; Lantuejoul, S.; Galateau Salle, F.; Meurgey, A.; Chassagne-Clement, C.; Treilleux, I.; Renard, C.; et al. Wholistic Approach: Transcriptomic Analysis and beyond Using Archival Material for Molecular Diagnosis. Genes Chromosomes Cancer 2022, 61, 382–393. [Google Scholar] [CrossRef]
- Le Loarer, F.; Pissaloux, D.; Watson, S.; Godfraind, C.; Galmiche-Rolland, L.; Silva, K.; Mayeur, L.; Italiano, A.; Michot, A.; Pierron, G.; et al. Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. Am. J. Surg. Pathol. 2019, 43, 268–276. [Google Scholar] [CrossRef] [PubMed]
- Le Loarer, F.; Cleven, A.H.G.; Bouvier, C.; Castex, M.-P.; Romagosa, C.; Moreau, A.; Salas, S.; Bonhomme, B.; Gomez-Brouchet, A.; Laurent, C.; et al. A Subset of Epithelioid and Spindle Cell Rhabdomyosarcomas Is Associated with TFCP2 Fusions and Common ALK Upregulation. Mod. Pathol. 2020, 33, 404–419. [Google Scholar] [CrossRef] [PubMed]
- Antonescu, C.R.; Rosenberg, A.E.; Xie, Z.; Zhang, L.; Perell, K.A.; Loya, A.C. Sarcomas with Sclerotic Epithelioid Phenotype Harboring Novel EWSR1-SSX1 Fusions. Genes Chromosomes Cancer 2021, 60, 616–622. [Google Scholar] [CrossRef] [PubMed]
- Demetri, G.D.; Antonescu, C.R.; Bjerkehagen, B.; Bovée, J.V.M.G.; Boye, K.; Chacón, M.; Dei Tos, A.P.; Desai, J.; Fletcher, J.A.; Gelderblom, H.; et al. Diagnosis and Management of Tropomyosin Receptor Kinase (TRK) Fusion Sarcomas: Expert Recommendations from the World Sarcoma Network. Ann. Oncol. 2020, 31, 1506–1517. [Google Scholar] [CrossRef]
- Dermawan, J.K.; Zou, Y.; Antonescu, C.R. Neuregulin 1 (NRG1) Fusion-Positive High-Grade Spindle Cell Sarcoma: A Distinct Group of Soft Tissue Tumors with Metastatic Potential. Genes Chromosomes Cancer 2022, 61, 123–130. [Google Scholar] [CrossRef]
- Karanian, M.; Pissaloux, D.; Gomez-Brouchet, A.; Chevenet, C.; Le Loarer, F.; Fernandez, C.; Minard, V.; Corradini, N.; Castex, M.-P.; Duc-Gallet, A.; et al. SRF-FOXO1 and SRF-NCOA1 Fusion Genes Delineate a Distinctive Subset of Well-Differentiated Rhabdomyosarcoma. Am. J. Surg. Pathol. 2020, 44, 607–616. [Google Scholar] [CrossRef]
- El Zein, S.; Djeroudi, L.; Reynaud, S.; Guillemot, D.; Masliah-Planchon, J.; Frouin, E.; Nicolas, N.; Le Loarer, F.; Daniel, C.; Delattre, O.; et al. Novel EWSR1::UBP1 Fusion Expands the Spectrum of Spindle Cell Rhabdomyosarcomas. Genes Chromosomes Cancer 2022, 61, 200–205. [Google Scholar] [CrossRef]
- Hirota, S.; Isozaki, K.; Moriyama, Y.; Hashimoto, K.; Nishida, T.; Ishiguro, S.; Kawano, K.; Hanada, M.; Kurata, A.; Takeda, M.; et al. Gain-of-Function Mutations of c-Kit in Human Gastrointestinal Stromal Tumors. Science 1998, 279, 577–580. [Google Scholar] [CrossRef]
- Joensuu, H.; Hohenberger, P.; Corless, C.L. Gastrointestinal Stromal Tumour. Lancet 2013, 382, 973–983. [Google Scholar] [CrossRef]
- von Mehren, M.; Joensuu, H. Gastrointestinal Stromal Tumors. J. Clin. Oncol. 2018, 36, 136–143. [Google Scholar] [CrossRef]
- Heinrich, M.C.; Corless, C.L.; Duensing, A.; McGreevey, L.; Chen, C.-J.; Joseph, N.; Singer, S.; Griffith, D.J.; Haley, A.; Town, A.; et al. PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors. Science 2003, 299, 708–710. [Google Scholar] [CrossRef] [PubMed]
- Kawaguchi, K.; Oda, Y.; Saito, T.; Takahira, T.; Yamamoto, H.; Tamiya, S.; Iwamoto, Y.; Tsuneyoshi, M. Genetic and Epigenetic Alterations of the PTEN Gene in Soft Tissue Sarcomas. Hum. Pathol. 2005, 36, 357–363. [Google Scholar] [CrossRef] [PubMed]
- Movva, S.; Wen, W.; Chen, W.; Millis, S.Z.; Gatalica, Z.; Reddy, S.; von Mehren, M.; Van Tine, B.A. Multi-Platform Profiling of over 2000 Sarcomas: Identification of Biomarkers and Novel Therapeutic Targets. Oncotarget 2015, 6, 12234–12247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Farid, M.; Demicco, E.G.; Garcia, R.; Ahn, L.; Merola, P.R.; Cioffi, A.; Maki, R.G. Malignant Peripheral Nerve Sheath Tumors. Oncologist 2014, 19, 193–201. [Google Scholar] [CrossRef] [Green Version]
- Pan, C.-C.; Chung, M.-Y.; Ng, K.-F.; Liu, C.-Y.; Wang, J.-S.; Chai, C.-Y.; Huang, S.-H.; Chen, P.C.-H.; Ho, D.M.T. Constant Allelic Alteration on Chromosome 16p (TSC2 Gene) in Perivascular Epithelioid Cell Tumour (PEComa): Genetic Evidence for the Relationship of PEComa with Angiomyolipoma. J. Pathol. 2008, 214, 387–393. [Google Scholar] [CrossRef]
- Giannikou, K.; Malinowska, I.A.; Pugh, T.J.; Yan, R.; Tseng, Y.-Y.; Oh, C.; Kim, J.; Tyburczy, M.E.; Chekaluk, Y.; Liu, Y.; et al. Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development. PLoS Genet. 2016, 12, e1006242. [Google Scholar] [CrossRef] [Green Version]
- Hornick, J.L.; Dal Cin, P.; Fletcher, C.D.M. Loss of INI1 Expression Is Characteristic of Both Conventional and Proximal-Type Epithelioid Sarcoma. Am. J. Surg. Pathol. 2009, 33, 542–550. [Google Scholar] [CrossRef]
- Margol, A.S.; Judkins, A.R. Pathology and Diagnosis of SMARCB1-Deficient Tumors. Cancer Genet. 2014, 207, 358–364. [Google Scholar] [CrossRef]
- Le Loarer, F.; Watson, S.; Pierron, G.; de Montpreville, V.T.; Ballet, S.; Firmin, N.; Auguste, A.; Pissaloux, D.; Boyault, S.; Paindavoine, S.; et al. SMARCA4 Inactivation Defines a Group of Undifferentiated Thoracic Malignancies Transcriptionally Related to BAF-Deficient Sarcomas. Nat. Genet. 2015, 47, 1200–1205. [Google Scholar] [CrossRef]
- Jelinic, P.; Mueller, J.J.; Olvera, N.; Dao, F.; Scott, S.N.; Shah, R.; Gao, J.; Schultz, N.; Gonen, M.; Soslow, R.A.; et al. Recurrent SMARCA4 Mutations in Small Cell Carcinoma of the Ovary. Nat. Genet. 2014, 46, 424–426. [Google Scholar] [CrossRef]
- Holdhof, D.; Johann, P.D.; Spohn, M.; Bockmayr, M.; Safaei, S.; Joshi, P.; Masliah-Planchon, J.; Ho, B.; Andrianteranagna, M.; Bourdeaut, F.; et al. Atypical Teratoid/Rhabdoid Tumors (ATRTs) with SMARCA4 Mutation Are Molecularly Distinct from SMARCB1-Deficient Cases. Acta Neuropathol. 2021, 141, 291–301. [Google Scholar] [CrossRef] [PubMed]
- Coindre, J.-M.; Pédeutour, F.; Aurias, A. Well-Differentiated and Dedifferentiated Liposarcomas. Virchows Arch. 2010, 456, 167–179. [Google Scholar] [CrossRef] [PubMed]
- Neuville, A.; Collin, F.; Bruneval, P.; Parrens, M.; Thivolet, F.; Gomez-Brouchet, A.; Terrier, P.; de Montpreville, V.T.; Le Gall, F.; Hostein, I.; et al. Intimal Sarcoma Is the Most Frequent Primary Cardiac Sarcoma: Clinicopathologic and Molecular Retrospective Analysis of 100 Primary Cardiac Sarcomas. Am. J. Surg. Pathol. 2014, 38, 461–469. [Google Scholar] [CrossRef] [PubMed]
- Momand, J.; Zambetti, G.P.; Olson, D.C.; George, D.; Levine, A.J. The Mdm-2 Oncogene Product Forms a Complex with the P53 Protein and Inhibits P53-Mediated Transactivation. Cell 1992, 69, 1237–1245. [Google Scholar] [CrossRef]
- Cissé, M.Y.; Pyrdziak, S.; Firmin, N.; Gayte, L.; Heuillet, M.; Bellvert, F.; Fuentes, M.; Delpech, H.; Riscal, R.; Arena, G.; et al. Targeting MDM2-Dependent Serine Metabolism as a Therapeutic Strategy for Liposarcoma. Sci. Transl. Med. 2020, 12, eaay2163. [Google Scholar] [CrossRef]
- Weaver, J.; Downs-Kelly, E.; Goldblum, J.R.; Turner, S.; Kulkarni, S.; Tubbs, R.R.; Rubin, B.P.; Skacel, M. Fluorescence in Situ Hybridization for MDM2 Gene Amplification as a Diagnostic Tool in Lipomatous Neoplasms. Mod. Pathol. 2008, 21, 943–949. [Google Scholar] [CrossRef] [Green Version]
- Hirata, M.; Asano, N.; Katayama, K.; Yoshida, A.; Tsuda, Y.; Sekimizu, M.; Mitani, S.; Kobayashi, E.; Komiyama, M.; Fujimoto, H.; et al. Integrated Exome and RNA Sequencing of Dedifferentiated Liposarcoma. Nat. Commun. 2019, 10, 5683. [Google Scholar] [CrossRef] [Green Version]
- Croce, S.; Ribeiro, A.; Brulard, C.; Noel, J.-C.; Amant, F.; Stoeckle, E.; Devouassoux-Shisheborah, M.; Floquet, A.; Arnould, L.; Guyon, F.; et al. Uterine Smooth Muscle Tumor Analysis by Comparative Genomic Hybridization: A Useful Diagnostic Tool in Challenging Lesions. Mod. Pathol. 2015, 28, 1001–1010. [Google Scholar] [CrossRef] [Green Version]
- Drilon, A.; Laetsch, T.W.; Kummar, S.; DuBois, S.G.; Lassen, U.N.; Demetri, G.D.; Nathenson, M.; Doebele, R.C.; Farago, A.F.; Pappo, A.S.; et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N. Engl. J. Med. 2018, 378, 731–739. [Google Scholar] [CrossRef]
- Hong, D.S.; DuBois, S.G.; Kummar, S.; Farago, A.F.; Albert, C.M.; Rohrberg, K.S.; van Tilburg, C.M.; Nagasubramanian, R.; Berlin, J.D.; Federman, N.; et al. Larotrectinib in Patients with TRK Fusion-Positive Solid Tumours: A Pooled Analysis of Three Phase 1/2 Clinical Trials. Lancet Oncol. 2020, 21, 531–540. [Google Scholar] [CrossRef]
- Marcus, L.; Donoghue, M.; Aungst, S.; Myers, C.E.; Helms, W.S.; Shen, G.; Zhao, H.; Stephens, O.; Keegan, P.; Pazdur, R. FDA Approval Summary: Entrectinib for the Treatment of NTRK Gene Fusion Solid Tumors. Clin. Cancer Res. 2021, 27, 928–932. [Google Scholar] [CrossRef] [PubMed]
- Mossé, Y.P.; Voss, S.D.; Lim, M.S.; Rolland, D.; Minard, C.G.; Fox, E.; Adamson, P.; Wilner, K.; Blaney, S.M.; Weigel, B.J. Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children’s Oncology Group Study. J. Clin. Oncol. 2017, 35, 3215–3221. [Google Scholar] [CrossRef] [PubMed]
- Schöffski, P.; Sufliarsky, J.; Gelderblom, H.; Blay, J.-Y.; Strauss, S.J.; Stacchiotti, S.; Rutkowski, P.; Lindner, L.H.; Leahy, M.G.; Italiano, A.; et al. Crizotinib in Patients with Advanced, Inoperable Inflammatory Myofibroblastic Tumours with and without Anaplastic Lymphoma Kinase Gene Alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): A Multicentre, Single-Drug, Prospective, Non-Randomised Phase 2 Trial. Lancet Respir. Med. 2018, 6, 431–441. [Google Scholar] [CrossRef] [PubMed]
- McArthur, G.A.; Demetri, G.D.; van Oosterom, A.; Heinrich, M.C.; Debiec-Rychter, M.; Corless, C.L.; Nikolova, Z.; Dimitrijevic, S.; Fletcher, J.A. Molecular and Clinical Analysis of Locally Advanced Dermatofibrosarcoma Protuberans Treated with Imatinib: Imatinib Target Exploration Consortium Study B2225. J. Clin. Oncol. 2005, 23, 866–873. [Google Scholar] [CrossRef]
- Navarrete-Dechent, C.; Mori, S.; Barker, C.A.; Dickson, M.A.; Nehal, K.S. Imatinib Treatment for Locally Advanced or Metastatic Dermatofibrosarcoma Protuberans: A Systematic Review. JAMA Derm. 2019, 155, 361–369. [Google Scholar] [CrossRef]
- Kérob, D.; Porcher, R.; Vérola, O.; Dalle, S.; Maubec, E.; Aubin, F.; D’Incan, M.; Bodokh, I.; Boulinguez, S.; Madelaine-Chambrin, I.; et al. Imatinib Mesylate as a Preoperative Therapy in Dermatofibrosarcoma: Results of a Multicenter Phase II Study on 25 Patients. Clin. Cancer Res. 2010, 16, 3288–3295. [Google Scholar] [CrossRef] [Green Version]
- Ugurel, S.; Mentzel, T.; Utikal, J.; Helmbold, P.; Mohr, P.; Pföhler, C.; Schiller, M.; Hauschild, A.; Hein, R.; Kämpgen, E.; et al. Neoadjuvant Imatinib in Advanced Primary or Locally Recurrent Dermatofibrosarcoma Protuberans: A Multicenter Phase II DeCOG Trial with Long-Term Follow-Up. Clin. Cancer Res. 2014, 20, 499–510. [Google Scholar] [CrossRef] [Green Version]
- Cassier, P.A.; Italiano, A.; Gomez-Roca, C.A.; Le Tourneau, C.; Toulmonde, M.; Cannarile, M.A.; Ries, C.; Brillouet, A.; Müller, C.; Jegg, A.-M.; et al. CSF1R Inhibition with Emactuzumab in Locally Advanced Diffuse-Type Tenosynovial Giant Cell Tumours of the Soft Tissue: A Dose-Escalation and Dose-Expansion Phase 1 Study. Lancet Oncol. 2015, 16, 949–956. [Google Scholar] [CrossRef]
- Tap, W.D.; Gelderblom, H.; Palmerini, E.; Desai, J.; Bauer, S.; Blay, J.-Y.; Alcindor, T.; Ganjoo, K.; Martín-Broto, J.; Ryan, C.W.; et al. Pexidartinib versus Placebo for Advanced Tenosynovial Giant Cell Tumour (ENLIVEN): A Randomised Phase 3 Trial. Lancet 2019, 394, 478–487. [Google Scholar] [CrossRef]
- Kang, Y.-K.; George, S.; Jones, R.L.; Rutkowski, P.; Shen, L.; Mir, O.; Patel, S.; Zhou, Y.; von Mehren, M.; Hohenberger, P.; et al. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J. Clin. Oncol. 2021, 39, 3128–3139. [Google Scholar] [CrossRef]
- Blay, J.-Y.; Serrano, C.; Heinrich, M.C.; Zalcberg, J.; Bauer, S.; Gelderblom, H.; Schöffski, P.; Jones, R.L.; Attia, S.; D’Amato, G.; et al. Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumours (INVICTUS): A Double-Blind, Randomised, Placebo-Controlled, Phase 3 Trial. Lancet Oncol. 2020, 21, 923–934. [Google Scholar] [CrossRef]
- Demetri, G.D.; von Mehren, M.; Blanke, C.D.; Van den Abbeele, A.D.; Eisenberg, B.; Roberts, P.J.; Heinrich, M.C.; Tuveson, D.A.; Singer, S.; Janicek, M.; et al. Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors. N. Engl. J. Med. 2002, 347, 472–480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Demetri, G.D.; van Oosterom, A.T.; Garrett, C.R.; Blackstein, M.E.; Shah, M.H.; Verweij, J.; McArthur, G.; Judson, I.R.; Heinrich, M.C.; Morgan, J.A.; et al. Efficacy and Safety of Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumour after Failure of Imatinib: A Randomised Controlled Trial. Lancet 2006, 368, 1329–1338. [Google Scholar] [CrossRef]
- Demetri, G.D.; Reichardt, P.; Kang, Y.-K.; Blay, J.-Y.; Rutkowski, P.; Gelderblom, H.; Hohenberger, P.; Leahy, M.; von Mehren, M.; Joensuu, H.; et al. Efficacy and Safety of Regorafenib for Advanced Gastrointestinal Stromal Tumours after Failure of Imatinib and Sunitinib: An International, Multicentre, Prospective, Randomised, Placebo-Controlled Phase 3 Trial (GRID). Lancet 2013, 381, 295–302. [Google Scholar] [CrossRef] [Green Version]
- Heinrich, M.C.; Jones, R.L.; Gelderblom, H.; George, S.; Schöffski, P.; von Mehren, M.; Zalcberg, J.R.; Kang, Y.-K.; Abdul Razak, A.R.; Trent, J.C.; et al. INTRIGUE: A Phase III, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Ripretinib versus Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumor Previously Treated with Imatinib. J. Clin. Oncol. 2022, 40, 359881. [Google Scholar] [CrossRef]
- Wagner, A.J.; Ravi, V.; Riedel, R.F.; Ganjoo, K.; Van Tine, B.A.; Chugh, R.; Cranmer, L.; Gordon, E.M.; Hornick, J.L.; Du, H.; et al. Nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors. J. Clin. Oncol. 2021, 39, 3660–3670. [Google Scholar] [CrossRef]
- Sanfilippo, R.; Jones, R.L.; Blay, J.-Y.; Le Cesne, A.; Provenzano, S.; Antoniou, G.; Mir, O.; Fucà, G.; Fumagalli, E.; Bertulli, R.; et al. Role of Chemotherapy, VEGFR Inhibitors, and MTOR Inhibitors in Advanced Perivascular Epithelioid Cell Tumors (PEComas). Clin. Cancer Res. 2019, 25, 5295–5300. [Google Scholar] [CrossRef]
- Świtaj, T.; Sobiborowicz, A.; Teterycz, P.; Klimczak, A.; Makuła, D.; Wągrodzki, M.; Szumera-Ciećkiewicz, A.; Rutkowski, P.; Czarnecka, A.M. Efficacy of Sirolimus Treatment in PEComa-10 Years of Practice Perspective. J. Clin. Med. 2021, 10, 3705. [Google Scholar] [CrossRef]
- Chi, S.N.; Bourdeaut, F.; Laetsch, T.W.; Fouladi, M.; Macy, M.E.; Makin, G.W.; Shukla, N.N.; Wetmore, C.; Margol, A.S.; Casanova, M.; et al. Phase I Study of Tazemetostat, an Enhancer of Zeste Homolog-2 Inhibitor, in Pediatric Pts with Relapsed/Refractory Integrase Interactor 1-Negative Tumors. J. Clin. Oncol. 2020, 38, 10525. [Google Scholar] [CrossRef]
- Gounder, M.; Schöffski, P.; Jones, R.L.; Agulnik, M.; Cote, G.M.; Villalobos, V.M.; Attia, S.; Chugh, R.; Chen, T.W.-W.; Jahan, T.; et al. Tazemetostat in Advanced Epithelioid Sarcoma with Loss of INI1/SMARCB1: An International, Open-Label, Phase 2 Basket Study. Lancet Oncol. 2020, 21, 1423–1432. [Google Scholar] [CrossRef]
- de Jonge, M.; de Weger, V.A.; Dickson, M.A.; Langenberg, M.; Le Cesne, A.; Wagner, A.J.; Hsu, K.; Zheng, W.; Macé, S.; Tuffal, G.; et al. A Phase I Study of SAR405838, a Novel Human Double Minute 2 (HDM2) Antagonist, in Patients with Solid Tumours. Eur. J. Cancer 2017, 76, 144–151. [Google Scholar] [CrossRef] [PubMed]
- Wagner, A.J.; Banerji, U.; Mahipal, A.; Somaiah, N.; Hirsch, H.; Fancourt, C.; Johnson-Levonas, A.O.; Lam, R.; Meister, A.K.; Russo, G.; et al. Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors. J. Clin. Oncol. 2017, 35, 1304–1311. [Google Scholar] [CrossRef] [PubMed]
- Eder, J.P.; Doroshow, D.B.; Do, K.T.; Keedy, V.L.; Sklar, J.S.; Glazer, P.; Bindra, R.; Shapiro, G.I. Clinical Efficacy of Olaparib in IDH1/IDH2-Mutant Mesenchymal Sarcomas. JCO Precis. Oncol. 2021, 5, 466–472. [Google Scholar] [CrossRef] [PubMed]
- Grünewald, T.G.P.; Cidre-Aranaz, F.; Surdez, D.; Tomazou, E.M.; de Álava, E.; Kovar, H.; Sorensen, P.H.; Delattre, O.; Dirksen, U. Ewing Sarcoma. Nat. Rev. Dis. Primers 2018, 4, 5. [Google Scholar] [CrossRef] [PubMed]
- Renzi, S.; Anderson, N.D.; Light, N.; Gupta, A. Ewing-like Sarcoma: An Emerging Family of Round Cell Sarcomas. J. Cell. Physiol. 2019, 234, 7999–8007. [Google Scholar] [CrossRef] [PubMed]
- Sbaraglia, M.; Righi, A.; Gambarotti, M.; Dei Tos, A.P. Ewing Sarcoma and Ewing-like Tumors. Virchows Arch. 2020, 476, 109–119. [Google Scholar] [CrossRef] [PubMed]
- Pierron, G.; Tirode, F.; Lucchesi, C.; Reynaud, S.; Ballet, S.; Cohen-Gogo, S.; Perrin, V.; Coindre, J.-M.; Delattre, O. A New Subtype of Bone Sarcoma Defined by BCOR-CCNB3 Gene Fusion. Nat. Genet. 2012, 44, 461–466. [Google Scholar] [CrossRef] [Green Version]
- Kao, Y.-C.; Owosho, A.A.; Sung, Y.-S.; Zhang, L.; Fujisawa, Y.; Lee, J.-C.; Wexler, L.; Argani, P.; Swanson, D.; Dickson, B.C.; et al. BCOR-CCNB3 Fusion Positive Sarcomas: A Clinicopathologic and Molecular Analysis of 36 Cases With Comparison to Morphologic Spectrum and Clinical Behavior of Other Round Cell Sarcomas. Am. J. Surg. Pathol. 2018, 42, 604–615. [Google Scholar] [CrossRef]
- Yoshimoto, M.; Graham, C.; Chilton-MacNeill, S.; Lee, E.; Shago, M.; Squire, J.; Zielenska, M.; Somers, G.R. Detailed Cytogenetic and Array Analysis of Pediatric Primitive Sarcomas Reveals a Recurrent CIC-DUX4 Fusion Gene Event. Cancer Genet. Cytogenet. 2009, 195, 1–11. [Google Scholar] [CrossRef]
- Antonescu, C.R.; Owosho, A.A.; Zhang, L.; Chen, S.; Deniz, K.; Huryn, J.M.; Kao, Y.-C.; Huang, S.-C.; Singer, S.; Tap, W.; et al. Sarcomas with CIC-Rearrangements Are a Distinct Pathologic Entity with Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am. J. Surg. Pathol. 2017, 41, 941–949. [Google Scholar] [CrossRef]
- Missiaglia, E.; Williamson, D.; Chisholm, J.; Wirapati, P.; Pierron, G.; Petel, F.; Concordet, J.-P.; Thway, K.; Oberlin, O.; Pritchard-Jones, K.; et al. PAX3/FOXO1 Fusion Gene Status Is the Key Prognostic Molecular Marker in Rhabdomyosarcoma and Significantly Improves Current Risk Stratification. J. Clin. Oncol. 2012, 30, 1670–1677. [Google Scholar] [CrossRef] [PubMed]
- Butel, T.; Karanian, M.; Pierron, G.; Orbach, D.; Ranchere, D.; Cozic, N.; Galmiche, L.; Coulomb, A.; Corradini, N.; Lacour, B.; et al. Integrative Clinical and Biopathology Analyses to Understand the Clinical Heterogeneity of Infantile Rhabdomyosarcoma: A Report from the French MMT Committee. Cancer Med. 2020, 9, 2698–2709. [Google Scholar] [CrossRef] [PubMed]
- Agaram, N.P.; LaQuaglia, M.P.; Alaggio, R.; Zhang, L.; Fujisawa, Y.; Ladanyi, M.; Wexler, L.H.; Antonescu, C.R. MYOD1-Mutant Spindle Cell and Sclerosing Rhabdomyosarcoma: An Aggressive Subtype Irrespective of Age. A Reappraisal for Molecular Classification and Risk Stratification. Mod. Pathol. 2019, 32, 27–36. [Google Scholar] [CrossRef] [PubMed]
- Koontz, J.I.; Soreng, A.L.; Nucci, M.; Kuo, F.C.; Pauwels, P.; van Den Berghe, H.; Dal Cin, P.; Fletcher, J.A.; Sklar, J. Frequent Fusion of the JAZF1 and JJAZ1 Genes in Endometrial Stromal Tumors. Proc. Natl. Acad. Sci. USA 2001, 98, 6348–6353. [Google Scholar] [CrossRef] [Green Version]
- Lee, C.-H.; Ou, W.-B.; Mariño-Enriquez, A.; Zhu, M.; Mayeda, M.; Wang, Y.; Guo, X.; Brunner, A.L.; Amant, F.; French, C.A.; et al. 14-3-3 Fusion Oncogenes in High-Grade Endometrial Stromal Sarcoma. Proc. Natl. Acad. Sci. USA 2012, 109, 929–934. [Google Scholar] [CrossRef] [Green Version]
- Brahmi, M.; Franceschi, T.; Treilleux, I.; Pissaloux, D.; Ray-Coquard, I.; Dufresne, A.; Vanacker, H.; Carbonnaux, M.; Meeus, P.; Sunyach, M.-P.; et al. Molecular Classification of Endometrial Stromal Sarcomas Using RNA Sequencing Defines Nosological and Prognostic Subgroups with Different Natural History. Cancers 2020, 12, 2604. [Google Scholar] [CrossRef]
- Cocco, E.; Scaltriti, M.; Drilon, A. NTRK Fusion-Positive Cancers and TRK Inhibitor Therapy. Nat. Rev. Clin. Oncol. 2018, 15, 731–747. [Google Scholar] [CrossRef]
- Lovly, C.M.; Gupta, A.; Lipson, D.; Otto, G.; Brennan, T.; Chung, C.T.; Borinstein, S.C.; Ross, J.S.; Stephens, P.J.; Miller, V.A.; et al. Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions. Cancer Discov. 2014, 4, 889–895. [Google Scholar] [CrossRef] [Green Version]
- Cupp, J.S.; Miller, M.A.; Montgomery, K.D.; Nielsen, T.O.; O’Connell, J.X.; Huntsman, D.; van de Rijn, M.; Gilks, C.B.; West, R.B. Translocation and Expression of CSF1 in Pigmented Villonodular Synovitis, Tenosynovial Giant Cell Tumor, Rheumatoid Arthritis and Other Reactive Synovitides. Am. J. Surg. Pathol. 2007, 31, 970–976. [Google Scholar] [CrossRef]
- West, R.B.; Rubin, B.P.; Miller, M.A.; Subramanian, S.; Kaygusuz, G.; Montgomery, K.; Zhu, S.; Marinelli, R.J.; De Luca, A.; Downs-Kelly, E.; et al. A Landscape Effect in Tenosynovial Giant-Cell Tumor from Activation of CSF1 Expression by a Translocation in a Minority of Tumor Cells. Proc. Natl. Acad. Sci. USA 2006, 103, 690–695. [Google Scholar] [CrossRef] [Green Version]
- Sankhala, K.K.; Blay, J.-Y.; Ganjoo, K.N.; Italiano, A.; Hassan, A.B.; Kim, T.M.; Ravi, V.; Cassier, P.A.; Rutkowski, P.; Sankar, N.; et al. A Phase I/II Dose Escalation and Expansion Study of Cabiralizumab (Cabira; FPA-008), an Anti-CSF1R Antibody, in Tenosynovial Giant Cell Tumor (TGCT, Diffuse Pigmented Villonodular Synovitis D-PVNS). J. Clin. Oncol. 2017, 35, 11078. [Google Scholar] [CrossRef]
- Perry, J.A.; Seong, B.K.A.; Stegmaier, K. Biology and Therapy of Dominant Fusion Oncoproteins Involving Transcription Factor and Chromatin Regulators in Sarcomas. Annu. Rev. Cancer Biol. 2019, 3, 299–321. [Google Scholar] [CrossRef]
- Knott, M.M.L.; Hölting, T.L.B.; Ohmura, S.; Kirchner, T.; Cidre-Aranaz, F.; Grünewald, T.G.P. Targeting the Undruggable: Exploiting Neomorphic Features of Fusion Oncoproteins in Childhood Sarcomas for Innovative Therapies. Cancer Metastasis Rev. 2019, 38, 625–642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Farag, S.; Smith, M.J.; Fotiadis, N.; Constantinidou, A.; Jones, R.L. Revolutions in Treatment Options in Gastrointestinal Stromal Tumours (GISTs): The Latest Updates. Curr. Treat. Options Oncol. 2020, 21, 55. [Google Scholar] [CrossRef]
- Heinrich, M.C.; Jones, R.L.; von Mehren, M.; Schöffski, P.; Serrano, C.; Kang, Y.-K.; Cassier, P.A.; Mir, O.; Eskens, F.; Tap, W.D.; et al. Avapritinib in Advanced PDGFRA D842V-Mutant Gastrointestinal Stromal Tumour (NAVIGATOR): A Multicentre, Open-Label, Phase 1 Trial. Lancet Oncol. 2020, 21, 935–946. [Google Scholar] [CrossRef]
- Avapritinib Approved for GIST Subgroup. Cancer Discov. 2020, 10, 334. [CrossRef] [Green Version]
- Kenerson, H.; Folpe, A.L.; Takayama, T.K.; Yeung, R.S. Activation of the MTOR Pathway in Sporadic Angiomyolipomas and Other Perivascular Epithelioid Cell Neoplasms. Hum. Pathol. 2007, 38, 1361–1371. [Google Scholar] [CrossRef] [Green Version]
- Italiano, A.; Delcambre, C.; Hostein, I.; Cazeau, A.L.; Marty, M.; Avril, A.; Coindre, J.-M.; Bui, B. Treatment with the MTOR Inhibitor Temsirolimus in Patients with Malignant PEComa. Ann. Oncol. 2010, 21, 1135–1137. [Google Scholar] [CrossRef]
- Wagner, A.J.; Malinowska-Kolodziej, I.; Morgan, J.A.; Qin, W.; Fletcher, C.D.M.; Vena, N.; Ligon, A.H.; Antonescu, C.R.; Ramaiya, N.H.; Demetri, G.D.; et al. Clinical Activity of MTOR Inhibition with Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of MTORC1 in Tumors. J. Clin. Oncol. 2010, 28, 835–840. [Google Scholar] [CrossRef]
- Bill, K.L.J.; Garnett, J.; Meaux, I.; Ma, X.; Creighton, C.J.; Bolshakov, S.; Barriere, C.; Debussche, L.; Lazar, A.J.; Prudner, B.C.; et al. SAR405838: A Novel and Potent Inhibitor of the MDM2:P53 Axis for the Treatment of Dedifferentiated Liposarcoma. Clin. Cancer Res. 2016, 22, 1150–1160. [Google Scholar] [CrossRef] [Green Version]
- Laroche, A.; Chaire, V.; Algeo, M.-P.; Karanian, M.; Fourneaux, B.; Italiano, A. MDM2 Antagonists Synergize with PI3K/MTOR Inhibition in Well-Differentiated/Dedifferentiated Liposarcomas. Oncotarget 2017, 8, 53968–53977. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dickson, M.A.; Schwartz, G.K.; Keohan, M.L.; D’Angelo, S.P.; Gounder, M.M.; Chi, P.; Antonescu, C.R.; Landa, J.; Qin, L.-X.; Crago, A.M.; et al. Phase 2 Trial of the CDK4 Inhibitor Palbociclib (PD0332991) at 125 Mg Dose in Well-Differentiated or Dedifferentiated Liposarcoma. JAMA Oncol. 2016, 2, 937–940. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Movva, S.; von Mehren, M.; Handorf, E.A.; Morgan, J.A.; Nathenson, M.; Thornton, K.A.; Tetzlaff, E.D.; Barker, E.; Thibodeau, L.; Harley, A.C.; et al. SAR-096: A Phase II Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL), and Leiomyosarcoma (LMS). J. Clin. Oncol. 2020, 38, 11544. [Google Scholar] [CrossRef]
- Cornillie, J.; Wozniak, A.; Li, H.; Gebreyohannes, Y.K.; Wellens, J.; Hompes, D.; Debiec-Rychter, M.; Sciot, R.; Schöffski, P. Anti-Tumor Activity of the MDM2-TP53 Inhibitor BI-907828 in Dedifferentiated Liposarcoma Patient-Derived Xenograft Models Harboring MDM2 Amplification. Clin. Transl. Oncol. 2020, 22, 546–554. [Google Scholar] [CrossRef] [PubMed]
- Laroche-Clary, A.; Chaire, V.; Algeo, M.-P.; Derieppe, M.-A.; Loarer, F.L.; Italiano, A. Combined Targeting of MDM2 and CDK4 Is Synergistic in Dedifferentiated Liposarcomas. J. Hematol. Oncol. 2017, 10, 123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abdul Razak, A.R.; Bauer, S.; Suarez, C.; Lin, C.-C.; Quek, R.; Hütter-Krönke, M.L.; Cubedo, R.; Ferretti, S.; Guerreiro, N.; Jullion, A.; et al. Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study. Clin. Cancer Res. 2022, 28, 1087–1097. [Google Scholar] [CrossRef]
- Chibon, F.; Lagarde, P.; Salas, S.; Pérot, G.; Brouste, V.; Tirode, F.; Lucchesi, C.; de Reynies, A.; Kauffmann, A.; Bui, B.; et al. Validated Prediction of Clinical Outcome in Sarcomas and Multiple Types of Cancer on the Basis of a Gene Expression Signature Related to Genome Complexity. Nat. Med. 2010, 16, 781–787. [Google Scholar] [CrossRef]
- Lesluyes, T.; Delespaul, L.; Coindre, J.-M.; Chibon, F. The CINSARC Signature as a Prognostic Marker for Clinical Outcome in Multiple Neoplasms. Sci. Rep. 2017, 7, 5480. [Google Scholar] [CrossRef] [Green Version]
- Tawbi, H.A.; Burgess, M.; Bolejack, V.; Tine, B.A.V.; Schuetze, S.M.; Hu, J.; D’Angelo, S.; Attia, S.; Riedel, R.F.; Priebat, D.A.; et al. Pembrolizumab in Advanced Soft-Tissue Sarcoma and Bone Sarcoma (SARC028): A Multicentre, Two-Cohort, Single-Arm, Open-Label, Phase 2 Trial. Lancet Oncol. 2017, 18, 1493–1501. [Google Scholar] [CrossRef]
- Becht, E.; Giraldo, N.A.; Lacroix, L.; Buttard, B.; Elarouci, N.; Petitprez, F.; Selves, J.; Laurent-Puig, P.; Sautès-Fridman, C.; Fridman, W.H.; et al. Estimating the Population Abundance of Tissue-Infiltrating Immune and Stromal Cell Populations Using Gene Expression. Genome Biol. 2016, 17, 218. [Google Scholar] [CrossRef]
- Petitprez, F.; de Reyniès, A.; Keung, E.Z.; Chen, T.W.-W.; Sun, C.-M.; Calderaro, J.; Jeng, Y.-M.; Hsiao, L.-P.; Lacroix, L.; Bougoüin, A.; et al. B Cells Are Associated with Survival and Immunotherapy Response in Sarcoma. Nature 2020, 577, 556–560. [Google Scholar] [CrossRef] [PubMed]
- Italiano, A.; Dinart, D.; Soubeyran, I.; Bellera, C.; Espérou, H.; Delmas, C.; Mercier, N.; Albert, S.; Poignie, L.; Boland, A.; et al. Molecular Profiling of Advanced Soft-Tissue Sarcomas: The MULTISARC Randomized Trial. BMC Cancer 2021, 21, 1180. [Google Scholar] [CrossRef] [PubMed]
- Capper, D.; Jones, D.T.W.; Sill, M.; Hovestadt, V.; Schrimpf, D.; Sturm, D.; Koelsche, C.; Sahm, F.; Chavez, L.; Reuss, D.E.; et al. DNA Methylation-Based Classification of Central Nervous System Tumours. Nature 2018, 555, 469–474. [Google Scholar] [CrossRef] [PubMed]
- Koelsche, C.; Schrimpf, D.; Stichel, D.; Sill, M.; Sahm, F.; Reuss, D.E.; Blattner, M.; Worst, B.; Heilig, C.E.; Beck, K.; et al. Sarcoma Classification by DNA Methylation Profiling. Nat. Commun. 2021, 12, 498. [Google Scholar] [CrossRef] [PubMed]
- Burns, J.; Wilding, C.P.; Jones, R.L.; Huang, P.H. Proteomic Research in Sarcomas-Current Status and Future Opportunities. Semin. Cancer Biol. 2020, 61, 56–70. [Google Scholar] [CrossRef]
- Jerby-Arnon, L.; Neftel, C.; Shore, M.E.; Weisman, H.R.; Mathewson, N.D.; McBride, M.J.; Haas, B.; Izar, B.; Volorio, A.; Boulay, G.; et al. Opposing Immune and Genetic Mechanisms Shape Oncogenic Programs in Synovial Sarcoma. Nat. Med. 2021, 27, 289–300. [Google Scholar] [CrossRef]
- Aynaud, M.-M.; Mirabeau, O.; Gruel, N.; Grossetête, S.; Boeva, V.; Durand, S.; Surdez, D.; Saulnier, O.; Zaïdi, S.; Gribkova, S.; et al. Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution. Cell Rep. 2020, 30, 1767–1779.e6. [Google Scholar] [CrossRef] [Green Version]
- Zhou, Y.; Yang, D.; Yang, Q.; Lv, X.; Huang, W.; Zhou, Z.; Wang, Y.; Zhang, Z.; Yuan, T.; Ding, X.; et al. Single-Cell RNA Landscape of Intratumoral Heterogeneity and Immunosuppressive Microenvironment in Advanced Osteosarcoma. Nat. Commun. 2020, 11, 6322. [Google Scholar] [CrossRef]
- Yofe, I.; Dahan, R.; Amit, I. Single-Cell Genomic Approaches for Developing the next Generation of Immunotherapies. Nat. Med. 2020, 26, 171–177. [Google Scholar] [CrossRef]
- Davis-Marcisak, E.F.; Deshpande, A.; Stein-O’Brien, G.L.; Ho, W.J.; Laheru, D.; Jaffee, E.M.; Fertig, E.J.; Kagohara, L.T. From Bench to Bedside: Single-Cell Analysis for Cancer Immunotherapy. Cancer Cell 2021, 39, 1062–1080. [Google Scholar] [CrossRef]
Sarcoma Subtype | Translocation | Genes | Oncogenic Mechanism |
---|---|---|---|
Ewing sarcoma | t (11; 22) (q24; q12) | EWSR1, FLI1 | Transcription factor |
t (21; 22) (q22; q12) | EWSR1, ERG | ||
t (16; 21) (p11; q22) | FUS, ERG | ||
DSRCT | t (11; 22) (p13; q12) | EWSR1, WT1 | Transcription factor |
Alveolar rhabdomyosarcoma | t (2;13) (q35; q14) | PAX3, FOXO1 | Transcription factor |
t (1; 13) (p36; q14) | PAX7, FOXO1 | ||
Clear cell sarcoma | t (12; 22) (q13; q12) | EWSR1, ATF1 | Transcription factor |
Extraskeletal myxoid chondrosarcoma | t (9; 22) (q22–31; q11–12) | EWSR1, NR4A3 | Transcription factor |
Myxoid liposarcoma | t (12; 22) (q13; q12) | EWSR1, CHOP | Transcription factor |
t (12; 16) (q13; p11) | FUS, CHOP | ||
Alveolar soft part sarcoma | t (X; 17) (p11.2; q25) | ASPL, TFE3 | Transcription factor |
PEComa | Xp11 rearrangement | *, TFE3 | Transcription factor |
Low grade fibromyxoid sarcoma | t (7; 16) (q33; p11) | FUS, CREB3L2 | Transcription factor |
Sclerosing epithelioid fibrosarcoma | t (11; 22) (p11; q12) | EWSR1, CREB3L1 | Transcription factor |
Low grade endometrial stromal tumor | t (7; 17) (p15; q21) | JAZF1, JJAZ1 | Transcription factor |
Synovial sarcoma | t (X; 18) (p11; q11) | SYT, SSX1, SSX2, SSX4 | Chromatin remodeling |
Congenital fibrosarcoma | t (12; 15) (p13; q25) | ETV6, NTRK3 | Tyrosine Kinase |
Inflammatory myofibroblastic tumor | t (2; 19) (p23; p13.1) | TPM4, ALK | Tyrosine Kinase |
t (1; 2) (q22–23; p23) | TPM3, ALK | ||
Dermatofibrosarcoma protuberans | t (17; 22) (q22; q13) | COL1A1, PDGFβ | Growth Factor |
PVNS/TGCT | t (1; 2) (p13; q37) | COL6A3, CSF1 | Growth Factor |
Sarcoma Subtype | Molecular Target | Targeted Therapy | Overall Response Rate | Clinical Use | References |
---|---|---|---|---|---|
NTRK-fused sarcoma | NTRK1/2/3 fusions | Entrectinib | 46% | FDA-approved | [39,40,41] |
74% (adults) | |||||
Larotrectinib | 94% (children) | FDA-approved | |||
IMT | ALK/ROS fusions | Crizotinib | 50% (adults) | Off-label use | [42,43] |
85% (children) | |||||
DFSP | COL1A1-PDGFB fusion | Imatinib | 67% (advanced phase) | FDA-approved | [44,45,46,47] |
40–60% (neoadjuvant) | |||||
PVNS/TGCT | COL6A3-CSF1 fusions | Emactuzumab | 86% | Not approved | [48,49] |
Pexidartinib | 39% | FDA-approved | |||
GIST | KIT mutations | Imatinib | 53.7% | FDA-approved | [50,51,52,53,54] |
Sunitinib | 7% | FDA-approved | |||
Regorafenib | 4.5% | FDA-approved | |||
Ripretinib | 9.4% (4th line) | FDA-approved | |||
Avapritinib | 17.1% (>2nd line) | Not approved | |||
GIST | PDGFRA D842V mutation | Avapritinib | 88% | FDA-approved | [55] |
PEComa | TSC1/2 mutation | Everolimus | 41% | Off-label use | [56,57,58] |
Sirolimus | 73% | Off-label use | |||
Nab-sirolimus | 39% | FDA-approved | |||
Epithelioid sarcoma | SMARCB1 mutation | Tazemetostat | 15% (adults) | FDA-approved | [59,60] |
MRT/ATRT | 17% (children) | ||||
DDLPS | MDM2 amplification | SAR405838 | <10% | Not approved | [61,62] |
MK-8242 | |||||
Mesenchymal sarcomas | IDH1-2 mutation | Olaparib | 17% | Not approved | [63] |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Vibert, J.; Watson, S. The Molecular Biology of Soft Tissue Sarcomas: Current Knowledge and Future Perspectives. Cancers 2022, 14, 2548. https://doi.org/10.3390/cancers14102548
Vibert J, Watson S. The Molecular Biology of Soft Tissue Sarcomas: Current Knowledge and Future Perspectives. Cancers. 2022; 14(10):2548. https://doi.org/10.3390/cancers14102548
Chicago/Turabian StyleVibert, Julien, and Sarah Watson. 2022. "The Molecular Biology of Soft Tissue Sarcomas: Current Knowledge and Future Perspectives" Cancers 14, no. 10: 2548. https://doi.org/10.3390/cancers14102548