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

Authors: Murali, R.; Chandramohan, R.; Möller, I.; Scholz, S. L.; Berger, M.; Huberman, K.; Viale, A.; Pirun, M.; Socci, N. D.; Bouvier, N.; Bauer, S.; Artl, M.; Schilling, B.; Schimming, T.; Sucker, A.; Schwindenhammer, B.; Grabellus, F.; Speicher, M. R.; Schaller, J.; Hillen, U.; Schadendorf, D.; Mentzel, T.; Cheng, D. T.; Wiesner, T.; Griewank, K. G.
Article 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 in 9 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.
Keywords: genetics; angiosarcoma; myc; mapk pathway
Journal Title: Oncotarget
Volume: 6
Issue: 34
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2015-11-03
Start Page: 36041
End Page: 36052
Language: English
DOI: 10.18632/oncotarget.5936
PROVIDER: scopus
PUBMED: 26440310
PMCID: PMC4742160
Notes: Export Date: 2 December 2015 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Agnes Viale
    205 Viale
  2. Rajmohan Murali
    155 Murali
  3. Mono Pirun
    16 Pirun
  4. Nancy Bouvier
    30 Bouvier
  5. Nicholas D Socci
    182 Socci
  6. Thomas Wiesner
    38 Wiesner
  7. Michael Forman Berger
    380 Berger
  8. Donavan Tai Suan Cheng
    51 Cheng