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.
Highlights
Alterations involving the MAPK pathway were identified in 18 (53%) tumors
Angiosarcomas arose in skin (n = 22), liver (n = 4), spleen, kidney, adrenal, thyroid, nasal cavity, lymph node and mediastinum (n = 1 each)
We identified a number of known genetic alterations in angiosarcomas, including MYC and KLT4 amplifications, RAS mutations, inactivating PTPRB mutations and an activating PLCG1 mutation
Summary
Alterations involving the MAPK pathway were identified in 18 (53%) tumors. In 9 tumors, hotspot mutations in KRAS (G12), HRAS (A59, Q61), NRAS (Q61), BRAF (V600) and MAPK1 (E322) were observed. CNAs, including focal amplifications in MAPK1/CRKL (chr22q11), CRAF (chr3p25) or broad chromosomal gains on chr including BRAF were seen in 8 tumors (Figures 1 + 2). One tumor showed an inactivating NF1 intragenic deletion as a mechanism for activating the MAPK pathway. The tumor positive for a KRAS G12D mutation harbored a known activating GNAQ R183Q mutation, albeit at varying allelic frequencies (KRAS G12D at 6%, GNAQ R183Q at 30%), suggesting that the sample may be heterogeneous and that the KRAS mutant allele may be present in a sub-clone. With the exception of the tumor with GNAQ and KRAS co-mutation, all MAPK-activating hotspot mutations appeared to be mutually exclusive of www.impactjournals.com/oncotarg
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