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Original Research| Volume 148, P230-238, May 2021

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Hypermutated tumours across 11 cancer types show three distinct immune subtypes

  • Author Footnotes
    1 These authors contributed equally to this work.
    Wangxiong Hu
    Correspondence
    Corresponding author. Fax: +86 571 87025026.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Jiani Chen
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Lina Qi
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
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  • Weiting Ge
    Affiliations
    Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
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  • Shu Zheng
    Affiliations
    Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
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  • Yanmei Yang
    Correspondence
    Corresponding author.
    Affiliations
    Key Laboratory of Reproductive and Genetics, Ministry of Education, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
Published:March 19, 2021DOI:https://doi.org/10.1016/j.ejca.2021.01.044

      Highlights

      • HM tumours fell into three distinct immune subtypes: HM1, HM2 and HM3.
      • HM3 tumours were correlated with CD8 T cell infiltration and prolonged survival.
      • HM2 tumours were correlated with stromal infiltration, EMT and poor outcome.

      Abstract

      Background

      Complete remission is observed in less than half of hypermutated (HM) tumours after immune checkpoint blockade therapy, indicating that HM tumours are very heterogeneous. Thus, there is an urgent requirement to decipher the unknown intrinsic HM tumour subtypes.

      Methods

      Statistical analysis was performed on somatic mutation data from 5519 tumours across 11 cancer types obtained from The Cancer Genome Atlas and 338 colorectal cancer (CRC) samples obtained from an Asian cohort. Samples with a tumour mutation burden >10 mut/Mb were classified as HM. A total of 1040 HM samples harbouring corresponding transcriptomes were used for non-negative matrix factorisation clustering. Tumour mutational burden, neoantigens, T cell receptor (TCR) diversity, stromal score and immune score were compared between the subtypes.

      Results

      HM tumours fell into three distinct immune subtypes: HM1, HM2 and HM3. HM3 tumours were correlated with increased CD8 T cell infiltration, high TCR diversity, a high immune score and prolonged survival. HM2 tumours were correlated with an abundant stromal component, epithelial–mesenchymal transition, TGFβ, angiogenesis hallmarks and poor outcomes. The infiltration of more CD8 T cells and increased chemokine expression in HM3 were validated in CRC by immunofluorescence.

      Conclusions

      These findings will facilitate the development of a subtype-oriented therapy strategy to enhance the treatment effect in the near future.

      Keywords

      Abbreviations:

      (BCR) (B cell receptor), (BLCA) (bladder urothelial carcinoma), (BRCA) (breast invasive carcinoma), (CESC) (cervical squamous cell carcinoma and endocervical adenocarcinoma), (CRC) (colorectal cancer), (CTLs) (cytotoxic tumour-infiltrating lymphocytes), (DEGs) (differentially expressed genes), (EMT) (epithelial–mesenchymal transition), (FDR) (false discovery rate), (GEO) (Gene Expression Omnibus), (GO) (Gene Ontology), (HM) (hypermutated), (HNSC) (head and neck squamous cell carcinoma), (HR) (hazard ratio), (ICI) (immune checkpoint inhibitor), (INDEL) (insertion and deletion), (ITH) (intratumoural heterogeneity), (KEGG) (Kyoto Encyclopedia of Genes and Genomes), (LUAD) (lung adenocarcinoma), (LUSC) (lung squamous cell carcinoma), (MSI-H) (microsatellite instability-high), (MSI-L) (microsatellite instability-low), (MSigDB) (molecular signatures database), (MSS) (microsatellite stable), (Mb) (million bases), (NMF) (non-negative matrix factorisation), (OS) (overall survival), (OV) (ovarian serous adenocarcinoma), (QN) (quantile normalisation), (SKCM) (skin cutaneous melanoma), (SNP) (single nucleotide polymorphism), (STAD) (stomach adenocarcinoma), (TAMs) (Tumour-associated macrophages), (TCGA) (The Cancer Genome Atlas), (TCR) (T cell receptor), (TILs) (tumour-infiltrating lymphocytes), (TIME) (tumour immune microenvironment), (TMB) (tumour mutational burden), (T-SNE) (t-distributed Stochastic Neighbor Embedding), (UCEC) (uterine corpus endometrial carcinoma)
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