Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer

Nat Commun. 2019 Jun 24;10(1):2764. doi: 10.1038/s41467-019-10680-5.

Abstract

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Disease Progression
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genomics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Janus Kinases / metabolism
  • Male
  • Middle Aged
  • Mutation
  • Precision Medicine / methods
  • STAT Transcription Factors / metabolism
  • Signal Transduction / genetics
  • Survival Analysis
  • Thyroid Carcinoma, Anaplastic / genetics*
  • Thyroid Carcinoma, Anaplastic / mortality
  • Thyroid Carcinoma, Anaplastic / pathology
  • Thyroid Carcinoma, Anaplastic / therapy
  • Thyroid Gland / pathology
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / mortality
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / therapy
  • Transcriptome / genetics*
  • Up-Regulation

Substances

  • Biomarkers, Tumor
  • STAT Transcription Factors
  • Janus Kinases