Abstract

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.

Highlights

  • Thyroid cancer (THCA) is the most common endocrine cancer and its global incidence has risen rapidly [1, 2]

  • The follicular thyroid cell type has been implicated in papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), poorly differentiated thyroid Cancer (PDTC) and anaplastic thyroid cancer (ATC)

  • negative matrix factorization (NMF) clustering of 477 RNAseq-based gene expression profiles downloaded from the the cancer genome atlas (TCGA) consortium was performed to identify key immune molecular subtypes underlying the heterogeneous THCA Related Genes (IRGs) expression profiles in reduced dimensions [15]

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Summary

Introduction

Thyroid cancer (THCA) is the most common endocrine cancer and its global incidence has risen rapidly [1, 2]. Despite the low death rate associated with thyroid cancer, its recurrence or progression rates are high, increasing morbidity and mortality rates in patients with THCA [4]. THCA has multiple histological types and subtypes affecting different cells, with distinct characteristics and prognosis [5]. Most thyroid cancers are not malignant, existing treatments do not sufficiently improve prognosis of patients with locally advanced or distant metastatic thyroid cancer. This has necessitated the search for highly sensitive therapies such as immunotherapy [6, 7]. Understanding the immunophenotypes of the THCA microenvironment will promote the effective application of immunotherapy in THCA

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