Targeted massively parallel sequencing of angiosarcomas reveals frequent activation of the mitogen activated protein kinase pathway.

// Rajmohan Murali 1,2 , Raghu Chandramohan 2 , Inga Moller 4 , Simone L. Scholz 5 , Michael Berger 1,2 , Kety Huberman 2 , Agnes Viale 2 , Mono Pirun 2 , Nicholas D. Socci 2 , Nancy Bouvier 2 , Sebastian Bauer 6 , Monika Artl 8 , Bastian Schilling 4 , Tobias Schimming 4 , Antje Sucker 4 , Benjamin Schwindenhammer 7 , Florian Grabellus 7 , Michael R. Speicher 8 , Jorg Schaller 10 , Uwe Hillen 4 , Dirk Schadendorf 4 , Thomas Mentzel 11 , Donavan T. Cheng 2 , Thomas Wiesner 3,9 and Klaus G. Griewank 4 1 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York NY, USA 2 Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York NY, USA 3 Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center, New York NY, USA 4 Department of Dermatology, UUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany 5 Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany 6 Department of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany and German Cancer Consortium (DKTK), Heidelberg, Germany 7 Institute of Pathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany 8 Institute of Human Genetics, Medical University of Graz, Graz, Austria 9 Department of Dermatology, Medical University of Graz, Graz, Austria 10 Dermatopathology Duisburg, Duisburg, Germany 11 Dermatopathology Friedrichshafen, Friedrichshafen, Germany Correspondence to: Rajmohan Murali, email: // Thomas Wiesner, email: // Klaus G. Griewank, email: // Keywords : angiosarcoma, genetics, MAPK pathway, MYC Received : August 10, 2015 Accepted : September 14, 2015 Published : September 30, 2015 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.