TY - JOUR
T1 - Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma
AU - Chan, Jason Yongsheng
AU - Lim, Jing Quan
AU - Yeong, Joe
AU - Ravi, Vinod
AU - Guan, Peiyong
AU - Boot, Arnoud
AU - Tay, Timothy Kwang Yong
AU - Selvarajan, Sathiyamoorthy
AU - Md Nasir, Nur Diyana
AU - Loh, Jie Hua
AU - Ong, Choon Kiat
AU - Huang, Dachuan
AU - Tan, Jing
AU - Li, Zhimei
AU - Ng, Cedric Chuan Young
AU - Tan, Thuan Tong
AU - Masuzawa, Mikio
AU - Sung, Ken Wing Kin
AU - Farid, Mohamad
AU - Quek, Richard Hong Hui
AU - Tan, Ngian Chye
AU - Teo, Melissa Ching Ching
AU - Rozen, Steven George
AU - Tan, Patrick
AU - Futreal, Andrew
AU - Teh, Bin Tean
AU - Soo, Khee Chee
N1 - Funding Information:
We would like to thank Wei Lin Goh, Jiancheng Hong, Liang Kai Koh, Wei Liu, and Jing Yi Lee, as well as staff members at the SingHealth Tissue Repository and SingHealth Advanced Molecular Pathology Laboratory for technical and administrative assistance. We also thank all of the patients who participated in this study. This work was supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC) under a Singapore Translational Research Investigator Award (NMRC/ STAR/0006/2009) and a Research Training Fellowship (NMRC/ Fellowship/0054/2017), as well as by the SingHealth Duke-NUS Academic Medical Centre and the Oncology ACP Nurturing Clinician Scientist Scheme (08-FY2017/P1/14-A28) and a SHF-Foundation Research Grant (SHF/FG653P/2017).
Funding Information:
We would like to thank Wei Lin Goh, Jiancheng Hong, Liang Kai Koh, Wei Liu, and Jing Yi Lee, as well as staff members at the SingHealth Tissue Repository and SingHealth Advanced Molecular Pathology Laboratory for technical and administrative assistance. We also thank all of the patients who participated in this study. This work was supported by the Singapore Ministry of Health?s National Medical Research Council (NMRC) under a Singapore Translational Research Investigator Award (NMRC/ STAR/0006/2009) and a Research Training Fellowship (NMRC/ Fellowship/0054/2017), as well as by the SingHealth Duke-NUS Academic Medical Centre and the Oncology ACP Nurturing Clinician Scientist Scheme (08-FY2017/P1/14-A28) and a SHF-Foundation Research Grant (SHF/FG653P/2017).
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/11/2
Y1 - 2020/11/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI139080
DO - 10.1172/JCI139080
M3 - Article
C2 - 33016928
AN - SCOPUS:85094952175
SN - 0021-9738
VL - 130
SP - 5833
EP - 5846
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -