Sporadic Breast Angiosarcoma With MYC Amplification on Extrachromosomal Circular DNA Detected Using Nanopore Sequencing in an Adolescent Female

Abstract

Angiosarcoma (AS) is a malignant vascular neoplasm comprising neoplastic endothelial cells accounting for 1%-4% of soft tissue sarcomas. While lymphedema-associated and post-irradiation ASs are almost always driven by a high-level amplification of MYC (8q24), sporadic ASs, including those of breast parenchymal origin, typically lack MYC amplification. Here, we report a case of sporadic breast MYC-amplified AS in a 19-year-old female with no history of lymphedema or irradiation, who was referred to our hospital for an enlarging right breast mass. After needle biopsy, the patient underwent right mastectomy and axillary lymphadenectomy. Microscopically, atypical endothelial cells proliferated and formed well-defined or slit-like vascular channels that invaded and dissected the breast parenchymal fat, ducts, and lobules. In a limited area, the tumor cells showed solid sheet-like proliferation with increased mitotic figures of 40 per 2 mm² with a small area of necrosis. Immunohistochemical analysis revealed strong positivity for c-Myc. Fluorescence in situ hybridization (FISH) with MYC break-apart probes showed a high-level 5' single signal amplification. The patient was disease-free 16 months post-surgery. Nanopore sequencing successfully detected not only a high-level amplification of the 8q24 region, including MYC, but also multiple structural variants of the 8q24 region. In-depth analysis revealed extrachromosomal circular DNA amplification including the MYC protein-coding region and upstream region but not the downstream region. We also performed methylation classification using nanopore-based methylation data to successfully categorize the tumor as AS. This case report highlights the potential utility of nanopore sequencing in the diagnosis of sarcomas.

Keywords: MYC; adolescent; angiosarcoma; extrachromosomal circular DNA; methylation; nanopore.