Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Abstract

IntroductionA comprehensive investigation of the genomic landscape of papillary thyroid carcinomas (PTC), the most common thyroid malignancy, was recently reported by The Cancer Genome Atlas Network (TCGA Network) (1). These well-differentiated tumors were found to have a low frequency of somatic alterations (2), with the majority harboring mutually exclusive activating mutations in BRAF (60%) and RAS-family genes (13%), as well as fusion oncoproteins, primarily involving receptor tyrosine kinases (RTKs) such as RET, NTRK1 or -3, and ALK. Distinct signaling and transcriptomic consequences were observed between BRAF V600E -like tumors, which showed higher MAPK transcriptional output and lower expression of genes involved in iodine metabolism, and RAS-like tumors, which had lower MAPK signaling and comparatively preserved expression of iodine-related genes.The TCGA study excluded poorly differentiated thryoid cancers (PDTCs) and anaplastic thyroid cancers (ATCs) from their analysis in order to focus on a homogeneous histological cohort that would provide sufficient power to identify low-frequency genomic events. Although PDTCs and ATCs account for approximately 5%-10% of thyroid cancers, they represent a major clinical challenge. Patients with PDTC and ATC have a mean survival after diagnosis of 3.2 and 0.5 years, respectively, and account for approximately a third of deaths caused by this disease (3). Virtually all cases are refractory to radioiodine therapy, and traditional chemotherapy and radiotherapy are of marginal benefit (4, 5).Molecularly targeted approaches are being tested in preclinical BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. METHODS.We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). RESULTS.Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs w...

Clinicopathologic Features of Fatal Non-Anaplastic Follicular Cell–Derived Thyroid Carcinomas

“…When compared with PTC, PDTC are associated with a higher mutation burden and a higher rate (40%) of telomerase reverse transcriptase (TERT) promoter mutations (19). The TERT promoter mutation is a molecular signature associated with aggressive clinical behavior, including a propensity for DM and disease-specific death (19,20).…”

Long noncoding RNAs: emerging players in thyroid cancer pathogenesis

“…For the past 30 years of study of molecular mechanisms, thyroid cancer facilitated understanding of various genetically deregulated genes of many pathways: among them, two key signaling pathways are at the heart of thyroid cancer pathogenesis. The mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/Akt pathways have been shown to be frequently altered by different mechanisms in thyroid cancer (Xing 2013, Fagin & Wells 2016, Landa et al 2016. PTC frequently harbors activating mutations in the genes such as RET/PTC, BRAF, RAS, etc., of the MAPK pathway (Grieco et al 1990, Xing 2005, Hou et al 2007, Agrawal et al 2014, Murugan et al 2016) except the ERK (Murugan et al 2009) and infrequently harbors mutation in the genes such as EGFR, P53, EIF1AX, PPM1D, CHEK2, NF1, etc., (Masago et al 2009, Ricarte-Filho et al 2012, Agrawal et al 2014 but not commonly in the genes of PI3K/Akt pathway (Xing 2010, Murugan et al 2015a.…”

“…FTC and ATC commonly harbor genetic mutations/amplifications/fusions in genes such as P53, RAS, ALK, PIK3CA, PTEN, AKT, PDK1, RASAL1, RET, NTRK1/3, PAX8-PPARγ, etc. (Hou et al 2007, Liu et al 2008, 2013a, Landa et al 2016. Recently, PDTC and ATC have been shown to harbor BRAF mutations: 33% and 45%, respectively (Landa et al 2016).…”

“…(Hou et al 2007, Liu et al 2008, 2013a, Landa et al 2016. Recently, PDTC and ATC have been shown to harbor BRAF mutations: 33% and 45%, respectively (Landa et al 2016). Thyroid cancers have been shown to be mutated in certain genes of the metabolic and regulatory pathways such as IDH1 (Hemerly et al 2010, Murugan et al 2010 and TERT (Landa et al 2013, Liu et al 2013b, Xing et al 2014, Qasem et al 2015, respectively.…”

Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences

“…Indeed, the ATC with RAS or other mutations tend to be BRAF-like, as defined by the BRS (a 71 gene panel that distinguishes BRAF V600E from RAS-mutant PTCs, highly correlated to the transcriptional output of the MAPK pathway). The major genomic complexity of ATC may account for the non-perfect correspondence between gene expression and the underlying driver mutation [5].…”