title: Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers.
abstract: 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 were BRAF-like irrespective of driver mutation.
  
  
  CONCLUSIONS
  These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality.
  
  
  BACKGROUND
  This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Tihana
authors.initials: T
authors.lastname: Ibrahimpasic
authors.forename: Laura
authors.initials: L
authors.lastname: Boucai
authors.forename: Rileen
authors.initials: R
authors.lastname: Sinha
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.forename: Ronak H
authors.initials: RH
authors.lastname: Shah
authors.forename: Snjezana
authors.initials: S
authors.lastname: Dogan
authors.forename: Julio C
authors.initials: JC
authors.lastname: Ricarte-Filho
authors.forename: Gnana P
authors.initials: GP
authors.lastname: Krishnamoorthy
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Ronald
authors.initials: R
authors.lastname: Ghossein
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D015977:Eukaryotic Initiation Factor-1 / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D059467:Transcriptome; D060449:Wnt Signaling Pathway; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D015977:Eukaryotic Initiation Factor-1; C026022:eukaryotic peptide initiation factor-1A; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D018631:ras Proteins