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

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 ( BRAF V600E 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.

Mechanisms of TERT Reactivation and Its Interaction with BRAFV600E

“…This repositioning of enhancer elements through rearrangement leads to massive transcriptional upregulation of TERT and strong chromatin remodeling of the affected region [45]. In support of this hypothesis, TERT promoter rearrangements were reported to result in the highest TERT expression level among somatic TERT aberrations [3,46]. TERT rearrangement with telomerase activation was first reported in an immortal fibroblast cell line in 2009 [47].…”

“…The prevalence of TERT promoter mutations is significantly higher in ATC and PDTC than in DTC [4,5]. Moreover, the TERT expression levels induced by promoter mutations have also been reported to be higher in ATC than in DTC, which may be due to the expansion of subclones with TERT promoter mutations in ATC [46,70]. In the pan-cancer study of the TCGA cohort, the proportion of samples without TERT expression was higher in PTC than in cancers of other organs; a total of 22% of analyzed tumors had neither detectable TERT expression nor ALT-related abnormalities, and 79% of PTC cases did not have them [3].…”

Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer

“…The TCGA study of PTC showed that BRAF and RAS mutations were highly correlated with different expression patterns, denoted by the BRAF-RAS score [19]. In contrast, Landa et al [4] reported that most ATCs display a BRAF-like gene expression pattern, regardless of mutational status, a finding recently confirmed by Yoo et al [26]. In line with these studies, we also found that 10/11 ATC cases in our study displayed a BRAF-like expression pattern, including one case with an NRAS mutation (Figure 1c).…”

Integrative Analysis of Methylation and Transcriptome Identified Epigenetically Regulated lncRNAs With Prognostic Relevance for Thyroid Cancer

“…Recent multi-omics analysis has demonstrated that THCA is a heterogeneous disease characterized by a high degree of molecular heterogeneity (Killock, 2014;Yoo et al, 2019), implying the potential of molecular profiling as a predictive factor in the diagnosis, prognosis and treatment response for THCA which will overcome the limitations of conventional clinical and histopathological features. mRNA and miRNA expression patterns have been widely investigated for a long time and many mRNA-or miRNA-based signatures have been identified to improve the diagnosis and prognosis of THCA (Santarpia et al, 2013;Han et al, 2018;Kim et al, 2018;Teng et al, 2018;Wang et al, 2019).…”