title: Identification of oncogenic mutations and gene fusions in the follicular variant of papillary thyroid carcinoma.
abstract: BACKGROUND
  The diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) is increasingly common. Recent studies have suggested that FVPTC is heterogeneous and comprises multiple tumor types with distinct biological behaviors and underlying genetics.
  
  
  OBJECTIVE
  The purpose of this work was to identify the prevalence of mutations and gene fusions in known oncogenes in a panel representative of the common spectrum of FVPTC diagnosed at an academic medical center and correlate the clinical and pathological features obtained at the initial diagnosis with the tumor genotype.
  
  
  METHODS
  We performed SNaPshot genotyping on a panel of 129 FVPTCs of ≥1 cm for 90 point mutations or small deletions in known oncogenes and tumor suppressors and identified gene fusions using an anchored multiplex PCR assay targeting a panel of rearranged oncogenes.
  
  
  RESULTS
  We identified a mutation or gene fusion in 70% (89 of 127) of cases. Mutations targeting the RAS family of oncogenes were the most frequently observed class of alterations, present in 36% (46 of 127) of cases, followed by BRAF mutation, present in 30% (38 of 127). We also detected oncogenic rearrangements not previously associated with FVPTC, including TFG-ALK and CREB3L2-PPARγ. BRAF mutation was significantly associated with unencapsulated tumor status.
  
  
  CONCLUSIONS
  These data support the hypothesis that FVPTC is composed of distinct biological entities, with one class being identified by BRAF mutation and support the use of clinical genotyping assays that detect a diverse array of rearrangements involving ALK and PPARγ. Additional studies are necessary to identify genetic drivers in the 30% of FVPTCs with no known oncogenic alteration and to better predict behavior in tumors with known genotypes.
authors.affiliation: Thyroid Unit (D.G.M., S.E.D., G.H.D.), Department of Medicine, Department of Pathology (D.D.-S., P.M.S., K.D.L., Z.Z., L.L., A.J.I.), and Department of Surgery (C.L.), Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: David G
authors.initials: DG
authors.lastname: McFadden
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Peter M
authors.initials: PM
authors.lastname: Sadow
authors.forename: Kerry D
authors.initials: KD
authors.lastname: Lynch
authors.forename: Carrie
authors.initials: C
authors.lastname: Lubitz
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Donovan
authors.forename: Zongli
authors.initials: Z
authors.lastname: Zheng
authors.forename: Long
authors.initials: L
authors.lastname: Le
authors.forename: A J
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Gilbert H
authors.initials: GH
authors.lastname: Daniels
mesh_terms: D000328:Adult; D000368:Aged; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D050596:Oncogene Fusion; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology