Immune gene signature delineates a subclass of thyroid cancer with unfavorable clinical outcomes

Thyroid cancer (THCA) is a heterogeneous disease with multiple clinical outcomes Immune cells regulate its progression. Three immunomolecular subtypes (C1, C2, C3) were identified in gene expression data sets from TCGA and GEO databases. Among them, subtype C3 had highest frequency of BRAF mutations, lowest frequency of RAS mutations, highest mutation load and shorter progression-free survival. Functional enrichment analysis for the genes revealed that C1 was up-regulated in the ERK cascade pathway, C2 was up-regulated in cell migration and proliferation pathways, while C3 was enriched in body fluid, protein regulation and response to steroid hormones functions. Notably, the three molecular subtypes exhibit differences in immune microenvironments as shown by timer database and analysis of immune expression signatures. The abundance of B_cell, CD4_Tcell, Neutrophil, Macrophage and Dendritic cells in C2 subtype were lower than in C1 and C3 subtypes Leukocyte fraction, proliferation macrophage regulation, lymphocyte infiltration, IFN gamma response and TGF beta response scores were significantly higher in C3 compared with C1 and C2 subtypes. Unlike C3 subtype, it was observed that C1 and C2 subtypes were significantly negatively correlated with most immune checkpoint genes in two different cohorts. The characteristic genes were differentially expressed between cancer cells, adjacent tissues, and metastatic tissues in different cohorts. In summary, THCA can be subclassified into three molecular subtypes with distinct histological types, genetic and transcriptional phenotypes, all of which have potential clinical implications.