title: Targeted massively parallel sequencing of angiosarcomas reveals frequent activation of the mitogen activated protein kinase pathway.
abstract: Angiosarcomas are rare malignant mesenchymal tumors of endothelial differentiation. The clinical behavior is usually aggressive and the prognosis for patients with advanced disease is poor with no effective therapies. The genetic bases of these tumors have been partially revealed in recent studies reporting genetic alterations such as amplifications of MYC (primarily in radiation-associated angiosarcomas), inactivating mutations in PTPRB and R707Q hotspot mutations of PLCG1. Here, we performed a comprehensive genomic analysis of 34 angiosarcomas using a clinically-approved, hybridization-based targeted next-generation sequencing assay for 341 well-established oncogenes and tumor suppressor genes. Over half of the angiosarcomas (n = 18, 53%) harbored genetic alterations affecting the MAPK pathway, involving mutations in KRAS, HRAS, NRAS, BRAF, MAPK1 and NF1, or amplifications in MAPK1/CRKL, CRAF or BRAF. The most frequently detected genetic aberrations were mutations in TP53 in 12 tumors(35%) and losses of CDKN2A in9 tumors (26%). MYC amplifications were generally mutually exclusive of TP53 alterations and CDKN2A loss and were identified in 8 tumors (24%), most of which (n = 7, 88%) arose post-irradiation. Previously reported mutations in PTPRB (n = 10, 29%) and one (3%) PLCG1 R707Q mutation were also identified. Our results demonstrate that angiosarcomas are a genetically heterogeneous group of tumors, harboring a wide range of genetic alterations. The high frequency of genetic events affecting the MAPK pathway suggests that targeted therapies inhibiting MAPK signaling may be promising therapeutic avenues in patients with advanced angiosarcomas.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Raghu
authors.initials: R
authors.lastname: Chandramohan
authors.affiliation: Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Möller
authors.affiliation: Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Simone L
authors.initials: SL
authors.lastname: Scholz
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Kety
authors.initials: K
authors.lastname: Huberman
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Mono
authors.initials: M
authors.lastname: Pirun
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bouvier
authors.affiliation: Department of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Artl
authors.affiliation: Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schimming
authors.affiliation: Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.affiliation: Institute of Pathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwindenhammer
authors.affiliation: Institute of Pathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Grabellus
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: Dermatopathology Duisburg, Duisburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaller
authors.affiliation: Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hillen
authors.affiliation: Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Dermatopathology Friedrichshafen, Friedrichshafen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mentzel
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Donavan T
authors.initials: DT
authors.lastname: Cheng
authors.affiliation: Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.affiliation: Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Griewank
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004789:Enzyme Activation; D005260:Female; D006394:Hemangiosarcoma / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D020928:Mitogen-Activated Protein Kinases
keywords: MAPK pathway; MYC; angiosarcoma; genetics