MULTI-OMIC CHARACTERISATION OF HUMAN ANGIOSARCOMA

Abstract

Angiosarcomas are rare, clinically-aggressive tumors with limited treatment options and dismal prognosis. This thesis presents an integrative approach to the study of patients with angiosarcomas in Singapore, incorporating information from clinico-pathological data, multi-omic sequencing, NanoString immuno-oncology profiling and multiplex immunohistochemistry for tumor-infiltrating immune cells. Approximately half of angiosarcomas arising from the head & neck (AS-HN) harbour UV-related mutational signatures, with correspondingly higher tumor mutational burden (TMB). NanoString profiling revealed three distinct clusters represented by lack (Clusters 1 and 2) or enrichment (Cluster 3) of immune-related signaling and immune cells. Clusters 1 and 3 comprised mostly primary AS-HN, frequently with evidence of UV-related DNA damage, therefore providing the rationale for checkpoint immunotherapy especially in the Cluster 3 subgroup with both high TMB and Tumor Inflammation Signature (TIS) scores. Cluster 2 was enriched with secondary angiosarcomas and exhibited upregulation of epigenetic and oncogenic signaling pathways. Extending the investigation to systemic and local immune responses, the neutrophil-lymphocyte ratio (NLR) was found to inform survival outcomes. Finally, a metagenomic approach which led to the discovery of human herpesvirus-7 in association with angiosarcomas is also described. In conclusion, molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.