Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma
Jason Yongsheng Chan, … , Bin Tean Teh, Khee Chee Soo
Jason Yongsheng Chan, … , Bin Tean Teh, Khee Chee Soo
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5833-5846. https://doi.org/10.1172/JCI139080.
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Research Article Genetics Oncology

Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma

Abstract

Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non–UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15+), macrophages (CD68+), cytotoxic T cells (CD8+), Tregs (FOXP3+), and PD-L1+ cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.

Authors

Jason Yongsheng Chan, Jing Quan Lim, Joe Yeong, Vinod Ravi, Peiyong Guan, Arnoud Boot, Timothy Kwang Yong Tay, Sathiyamoorthy Selvarajan, Nur Diyana Md Nasir, Jie Hua Loh, Choon Kiat Ong, Dachuan Huang, Jing Tan, Zhimei Li, Cedric Chuan-Young Ng, Thuan Tong Tan, Mikio Masuzawa, Ken Wing-Kin Sung, Mohamad Farid, Richard Hong Hui Quek, Ngian Chye Tan, Melissa Ching Ching Teo, Steven George Rozen, Patrick Tan, Andrew Futreal, Bin Tean Teh, Khee Chee Soo

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Figure 6

Metagenomic identification of HHV-7 in human angiosarcoma.

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Metagenomic identification of HHV-7 in human angiosarcoma. (A) Viral rea...
(A) Viral reads mapped to the HHV-7 genome were detected in the metagenome of scalp angiosarcoma AS-01. (B) The presence of HHV-7 was verified by PCR and/or IHC (scale bars: 20 μm) in 11 of 18 patients (61.1%) in the discovery cohort. (C) Inflammation-related pathways, including “allograft rejection” (NES = 2.17, FDR Q < 0.001, P < 0.001), “interferon gamma response” (NES = 2.16, FDR Q < 0.001, P < 0.001), and “interferon alpha response” (NES = 2.06, FDR Q < 0.001, P < 0.001) were significantly enriched in HHV-7+ angiosarcomas. Virus-negative tumors were enriched for cell cycle–related pathways, including “Myc targets v1” (NES = –1.95, FDR Q < 0.001, P < 0.001), “E2F targets” (NES = –1.87, FDR Q < 0.001, P < 0.001), and “Myc targets v2” (NES = –1.87, FDR Q < 0.001, P < 0.001). (D) HHV-7+ angiosarcomas had lower levels of C>T mononucleotide substitutions (Mann-Whitney U, P = 0.0333) and CC>TT dinucleotide substitutions (Mann-Whitney U, P = 0.0127). (E) Compared with HHV-7– cases, HHV-7+ angiosarcomas were associated with high TIS scores (66.7% vs. 29.4%, χ2, P = 0.0242) and were overrepresented in cluster 3 (χ2 for trend, P = 0.0497). (F) Virus-positive tumors were strongly enriched for the myeloid compartment, with top cell-type scores for mast cells, macrophages, and neutrophils.