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Angiosarcoma : Molecular Genetics

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Angiosarcoma is genetically heterogenous with different clinical subtypes showing non-overlapping genetic abnormalities. Gene expression profiling studies have shown up-regulation of several genes linked to angiogenesis and endothelial differentiation. These include genes for vascular specific receptor tyrosine kinases: FLT1 (VEGFR1), KDR (VEGFR2), TIE1, SNRK, and TEK.

Recurrent somatic mutations have been identified in KDR, PTPRB, and PLCG1 genes in about 40% of cases. These genes are involved in angiogenic signaling pathways. PTPRB mutations, with or without co-existing R707Q hotspot PLCG1 mutations, have been reported exclusively in secondary or radiation-associated/MYC-amplified angiosarcomas. Activating KDR mutations and PLCG1 mutations are seen in about 10% of angiosarcomas, both primary and secondary tumors, but restricted to breast, bone, and viscera. KDR and PLCG1 genes are involved in the VEGFR2 signaling pathway and their mutations appear to be mutually exclusive.

Amplification of MYC oncogene (on 8q24.21) is a hallmark of post-radiation and chronic lymphedema-associated angiosarcomas, especially following treatment for breast cancer (91% of cases). This abnormality is seen in only a small percentage of angiosarcomas secondary to radiation for other tumor types (lymphoma, hemangiomatosis, salivary gland carcinoma, germ cell tumor, and prostate cancer) and in primary angiosarcomas (7% of cases).

MYC amplification can be detected by fluorescence in-situ hybridization or by immunohistochemistry. MYC amplification is useful in separating post-radiation angiosarcomas (MYC amplified) from other radiation-induced conditions such as atypical vascular lesion (no MYC amplification). In about 25% of post-radiation angiosarcomas, there is co-amplification of FLT4 which codes for VEGFR3. FLT4-amplified angiosarcomas usually have solid, high-grade phenotype with epithelioid or spindle cell morphology.

The image shows C-Myc amplification by immunohistochemistry in post-radiation angiosarcoma of breast. Image courtesy of: Brendan Dickson, MD, Dept. of Pathology, University of Toronto, Ontario, Canada; Used with permission.

Reference: Huang, SC et al. Recurrent CIC Gene Abnormalities in Angiosarcoma : A Molecular Study of 120 Cases with Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations. Am J Surg Pathol. 2016 May; 40(5):645-655.

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