MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema

Abstract

Angiosarcomas (AS) are rare vascular malignancies that arise either de novo as primary tumors or secondary to irradiation or chronic lymphedema. The cytogenetics of angiosarcomas are poorly characterized. We applied array-comparative genomic hybridization as a screening method to identify recurrent alterations in 22 cases. Recurrent genetic alterations were identified only in secondary but not in primary AS. The most frequent recurrent alterations were high level amplifications on chromosome 8q24.21 (50%), followed by 10p12.33 (33%) and 5q35.3 (11%). Fluorescence in situ hybridization analysis in 28 primary and 33 secondary angiosarcomas (31 tumors secondary to irradiation, 2 tumors secondary to chronic lymphedema) confirmed high level amplification of MYC on chromosome 8q24.21 as a recurrent genetic alteration found exclusively in 55% of AS secondary to irradiation or chronic lymphedema, but not in primary AS. Amplification of MYC did not predispose to high grade morphology or increased cell turnover. In conclusion, despite their identical morphology, secondary AS are genetically different from primary AS and are characterized by a high frequency of high level amplifications of MYC. This finding may have implications both for the diagnosis and treatment of these tumors.

Figure 1

DNA-copy number profiles of two representative angiosarcoma cases. Log2 copy number ratios of tumor versus an opposite sex diploid control genome were plotted on the y axis against 10,000 chromosome fragments in chromosomal order on the x axis. Log2-ratios above 0 indicate copy-number gains, below zero copy number losses. Upper panel: primary angiosarcoma showing several small low-level copy number gains and losses. Lower panel: radiation induced angiosarcoma displaying partial amplification of chromosome band 5q35.3 and of the MYC locus at 8q.24.21.

Figure 2

Morphology and fluorescence in situ hybridization analysis in primary and secondary angiosarcomas. A: Representative image of an angiosarcoma (FNCLCC grade 2) showing endothelial tumor cells growing in anastomosing, dissecting channels (primary retroperitoneal angiosarcoma). Primary and secondary angiosarcomas were morphologically undistinguishable. B: Inter- and metaphase nuclei (blue) of a primary angiosarcoma without MYC amplification. C: Interphase nuclei (blue) of a radiation-induced angiosarcoma with high level amplification of MYC (magenta signals) compared with the probe for the centromeric region of chromosome 8 (green signals).