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...

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Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphologic spectrum of 47 sinonasal tumors including 17 (36.2%) SNUCs were analyzed at genomic level. Thirty carcinomas (Cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACT™) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumors (Cohort 2) were examined only for presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in 2 (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of 2 high-grade neuroendocrine carcinomas, large cell type (HGNEC). No IDH2 mutation was detected in any of 5 olfactory neuroblastomas or in any of 5 SMARCB1–deficient carcinomas. Among 12 IDH2-mutated cases in Cohort 1, 5 (41.7%) harbored co-existing TP53 mutations, 4 (33.3%) CDKN2A/2B loss-of-function alterations, 4 (33.3%) MYC amplification, and 3 (25%) had concurrent SETD2 mutations. AKT1 E17K and KIT D816V hotspot variants were each detected in one IDH2-mutated SNUC. The vast majority of SNUCs and variable proportions of other poorly differentiated sinonasal carcinomas may be amenable to IDH2-targeted therapy.