Benjamin Bonhomme1, Yann Godbert2, Gaelle Perot1, Abir Al Ghuzlan3, Stéphane Bardet4, Geneviève Belleannée5, Lise Crinière6, Christine Do Cao7, Geneviève Fouilloux8, Serge Guyetant9, Antony Kelly10, Sophie Leboulleux11, Camille Buffet12, Emmanuelle Leteurtre13, Jean-Jacques Michels14, Frédérique Tissier15, Marie-Elisabeth Toubert16, Michel Wassef17, Clémence Pinard1, Isabelle Hostein1, Isabelle Soubeyran1. 1. 1 Department of Biopathology, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France . 2. 2 Nuclear Medicine and Thyroid Oncology Unit, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France . 3. 3 Department of Pathology, Institut Gustave Roussy , Villejuif, France . 4. 4 Department of Nuclear Medicine, Centre François Baclesse , Caen, France . 5. 5 Department of Pathology, Bordeaux University Hospital Center Haut-Lévêque , Pessac, France . 6. 6 Department of Endocrinology, Diabetes and Metabolism, University Hospital Center of Tours , Tours, France . 7. 7 Department of Endocrinology, Diabetes, and Metabolism, Lille University Hospital Center Claude Huriez , Lille, France . 8. 8 Department of Pathology, Institut Jean Perrin , Clermont-Ferrand, France . 9. 9 Department of Pathology, University Hospital Center of Tours , Tours, France . 10. 10 Department of Nuclear Medicine, Institut Jean Perrin , Clermont-Ferrand, France . 11. 11 Department of Nuclear Medicine, Institut Gustave Roussy , Villejuif, France . 12. 12 Thyroid and Endocrine Tumors Unit, Endocrinology Institute, Paris University Hospital Center Pitié-Salpêtrière , Paris, France . 13. 13 University of Lille , Inserm, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille, France . 14. 14 Department of Biopathology, Centre François Baclesse , Caen, France . 15. 15 Department of Pathology, Paris University Hospital Center Pitié-Salpêtrière , Paris, France . 16. 16 Department of Nuclear Medicine, Paris University Hospital Center Saint-Louis-Lariboisière , Paris, France . 17. 17 Department of Pathology, Paris University Hospital Center Saint-Louis-Lariboisière , Paris, France .
Abstract
BACKGROUND: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSION: 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: Alyaksandr V Nikitski; Susan L Rominski; Vincenzo Condello; Cihan Kaya; Mamta Wankhede; Federica Panebianco; Hong Yang; Daniel L Altschuler; Yuri E Nikiforov Journal: Thyroid Date: 2019-08-16 Impact factor: 6.568
Authors: Emily Greengard; Yael P Mosse; Xiaowei Liu; Charles G Minard; Joel M Reid; Stephan Voss; Keith Wilner; Elizabeth Fox; Frank Balis; Susan M Blaney; Peter C Adamson; Brenda J Weigel Journal: Cancer Chemother Pharmacol Date: 2020-10-23 Impact factor: 3.333
Authors: Daniela De Martino; Emrullah Yilmaz; Arturo Orlacchio; Michela Ranieri; Ke Zhao; Antonio Di Cristofano Journal: Cancer Lett Date: 2018-09-19 Impact factor: 8.679
Authors: Christine Dierks; Jochen Seufert; Konrad Aumann; Juri Ruf; Claudius Klein; Selina Kiefer; Michael Rassner; Melanie Boerries; Andreas Zielke; Paul la Rosee; Philipp Tobias Meyer; Matthias Kroiss; Christian Weißenberger; Tilmann Schumacher; Patrick Metzger; Harald Weiss; Constantin Smaxwil; Katharina Laubner; Justus Duyster; Nikolas von Bubnoff; Cornelius Miething; Oliver Thomusch Journal: Thyroid Date: 2021-04-15 Impact factor: 6.568
Authors: Keith C Bible; Electron Kebebew; James Brierley; Juan P Brito; Maria E Cabanillas; Thomas J Clark; Antonio Di Cristofano; Robert Foote; Thomas Giordano; Jan Kasperbauer; Kate Newbold; Yuri E Nikiforov; Gregory Randolph; M Sara Rosenthal; Anna M Sawka; Manisha Shah; Ashok Shaha; Robert Smallridge; Carol K Wong-Clark Journal: Thyroid Date: 2021-03 Impact factor: 6.568