title: Molecular Pathology of Anaplastic Thyroid Carcinomas: A Retrospective Study of 144 Cases.
abstract: Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations.
  
  
  
  One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened.
  
  
  
  Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest.
  
  
  
  This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.
authors.affiliation: 1 Department of Biopathology, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonhomme
authors.affiliation: 2 Nuclear Medicine and Thyroid Oncology Unit, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
authors.forename: Yann
authors.initials: Y
authors.lastname: Godbert
authors.affiliation: 1 Department of Biopathology, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
authors.forename: Gaelle
authors.initials: G
authors.lastname: Perot
authors.affiliation: 3 Department of Pathology, Institut Gustave Roussy , Villejuif, France .
authors.forename: Abir
authors.initials: A
authors.lastname: Al Ghuzlan
authors.affiliation: 4 Department of Nuclear Medicine, Centre François Baclesse , Caen, France .
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bardet
authors.affiliation: 5 Department of Pathology, Bordeaux University Hospital Center Haut-Lévêque , Pessac, France .
authors.forename: Geneviève
authors.initials: G
authors.lastname: Belleannée
authors.affiliation: 6 Department of Endocrinology, Diabetes and Metabolism, University Hospital Center of Tours , Tours, France .
authors.forename: Lise
authors.initials: L
authors.lastname: Crinière
authors.affiliation: 7 Department of Endocrinology, Diabetes, and Metabolism, Lille University Hospital Center Claude Huriez , Lille, France .
authors.forename: Christine
authors.initials: C
authors.lastname: Do Cao
authors.affiliation: 8 Department of Pathology, Institut Jean Perrin , Clermont-Ferrand, France .
authors.forename: Geneviève
authors.initials: G
authors.lastname: Fouilloux
authors.affiliation: 9 Department of Pathology, University Hospital Center of Tours , Tours, France .
authors.forename: Serge
authors.initials: S
authors.lastname: Guyetant
authors.affiliation: 10 Department of Nuclear Medicine, Institut Jean Perrin , Clermont-Ferrand, France .
authors.forename: Antony
authors.initials: A
authors.lastname: Kelly
authors.affiliation: 11 Department of Nuclear Medicine, Institut Gustave Roussy , Villejuif, France .
authors.forename: Sophie
authors.initials: S
authors.lastname: Leboulleux
authors.affiliation: 12 Thyroid and Endocrine Tumors Unit, Endocrinology Institute, Paris University Hospital Center Pitié-Salpêtrière , Paris, France .
authors.forename: Camille
authors.initials: C
authors.lastname: Buffet
authors.affiliation: 13 University of Lille , Inserm, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille, France .
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.affiliation: 14 Department of Biopathology, Centre François Baclesse , Caen, France .
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Michels
authors.affiliation: 15 Department of Pathology, Paris University Hospital Center Pitié-Salpêtrière , Paris, France .
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.affiliation: 16 Department of Nuclear Medicine, Paris University Hospital Center Saint-Louis-Lariboisière , Paris, France .
authors.forename: Marie-Elisabeth
authors.initials: ME
authors.lastname: Toubert
authors.affiliation: 17 Department of Pathology, Paris University Hospital Center Saint-Louis-Lariboisière , Paris, France .
authors.forename: Michel
authors.initials: M
authors.lastname: Wassef
authors.affiliation: 1 Department of Biopathology, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
authors.forename: Clémence
authors.initials: C
authors.lastname: Pinard
authors.affiliation: 1 Department of Biopathology, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hostein
authors.affiliation: 1 Department of Biopathology, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
authors.forename: Isabelle
authors.initials: I
authors.lastname: Soubeyran
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D057089:Pathology, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase
keywords: ALK; anaplastic thyroid carcinoma; mutations; new-generation sequencing; thyroid; translocation