Have represented low-frequency germline polymorphisms. A single truncating mutation in APC (p.Q1529X) was discovered in an ATC with an unusually higher mutation burden. Furthermore, our results usually do not help a relevant role for mutations in genes inside the apoptosis, Hedgehog, homologous recombination, immune response, insulin-like, JAK-STAT, tricarboxylic acid, nucleotide excision repair, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/20186201 polycomb, ubiquitination, or TGF pathways in PDTC and ATC tumorigenesis. With respect to mutations reported in single cases in a recent exome sequencing study of ATCs (21), we replicated these findings inside the cyclin-dependent kinase inhibitors CDKN1B and CDKN2C(and found an additional truncating mutation in CDKN2A), as well as in other genes such as ERBB2, PTCH1, and DAXX (Supplemental Figure 1), but not in TRAF7 and NCOR1.Gene fusions Chromosomal rearrangements involving genes known to be translocated in thyroid tumors were frequent events in PDTCs (14 ) but were absent in ATCs and did not overlap with BRAF, RAS, TSHR, or STK11 mutations (Figure 1D). RET/PTC rearrangements were detected in 5 PDTCs and involved the most common RET partners CCDC6 and NCOA4. Translocations leading to PAX8-PPARG fusions were observed in 3 PDTCs, whereas fusions involving ALK gene were detected in another 3 tumors. The kinase domain of ALK was recombined with three different upstream partners, including the known STRN and EML4, as well as CCDC149, a novel ALK fusion partner, which is a coiled-coil family gene located on chromosome 4 (fusion included CCDC149 exons 10 and ALK exons 209). The 11 PDTCs harboring gene fusions occurred in younger patients (49 vs. 58 years, P = 0.04; Supplemental Table 5). A single ATC without known driver mutations carried a t(15;19)(q13;p13.1) translocation involving the NUT gene (NUTM1, NUT midline carcinoma, family member 1) and BRD4 (bromojci.org Volume 126 Number 3 March 2016CliniCal MediCineThe Journal of Clinical InvestigationTable 3. Contingency analysis of TERT-BRAF/RAS mutations in thyroid cancers PTC-TCGAA TERT WTBRAF/RAS WT BRAF/RAS mutant Total 103 243PDTC + ATCB Total107 274TERT mutant4 31TERT WT29 30TERT mutant13 45Total42 75A Papillary thyroid cancers from the TCGA study (1), n = 381. BPDTC and ATC from the current study (n = 84 + 33). TERT and BRAF/RAS mutations significantly co-occur both in PTCs (contingency test: OR = 3.3; P = 0.03) and in PDTCs and ATCs combined (contingency test: OR = 3.4; P = 0.004). Odds ratios and P values are derived from 2-tailed Fisher’s exact tests.domain containing 4), resulting in an in-frame NUT-BRD4 fusion (NUT exons 1 and BRD4 exons 140). It was detected in an ATC with areas of PDTC in a 34-year-old woman who underwent total thyroidectomy and laryngopharyngectomy, plus radiotherapy, and who is alive 10 years after diagnosis. It clearly represents an outlier from the clinical behavior standpoint, which matches with her unique genetic alteration, involved in large-scale chromatin remodeling (34).Somatic CNAs Tumor purity of PDTCs was similar to PTCs (median tumor content 74 and 72 , respectively) whereas it was much lower in ATCs (42 ) (Supplemental Figure 2). By correcting for tumor purity, we greatly enhanced our order BMS-214662 sensitivity for detecting CNAs even in most of the heavily infiltrated ATCs, as well as in some PDTCs. The ability of IMPACT to call arm-level CNAs was explored in 37 tumors that were simultaneously profiled by array-CGH. As seen in Supplemental Figure 3, CNA calls were efficiently replicated.