Molecular pathology of anaplastic thyroid carcinomas: a retrospective study of 144 cases.

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Molecular pathology of anaplastic thyroid carcinomas: a retrospective study of 144 cases.

Thyroid. 2017 Mar 28;:

Authors: Bonhomme B, Godbert Y, Perot G, Alghuzlan A, Bardet S, Belleannée G, Criniere L, Do Cao C, Fouilhoux G, Guyetant S, Kelly A, Leboulleux S, Buffet C, Leteurtre E, Michels JJ, Tissier F, Toubert ME, Wassef M, Pinard C, Hostein I, Soubeyran I

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 aim of this retrospective study was to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and identify the mutational profile of ATC including TERT promoter mutation.
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 (TUTHYREF). Fluorescence in situ hybridization (FISH) analysis for ALK rearrangement was performed on Tissue Micro Arrays (TMA). A panel of 50 genes using next generation sequencing (NGS) and TERT promoter mutations using Sanger sequencing were also screened.
RESULTS: FISH was interpretable for 90 cases (62.5%). One case (1.1%) was positive for ALK rearrangement with a borderline threshold (15% positive cells). NGS results were interpretable for 94 cases (65.3%) and Sanger sequencing (TERT) for 98 cases (68.1%). 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.(Val600Glu)), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations and 4.3% both TP53 and PTEN mutations. Nearly 10 percent of the cases showed no mutations of the RAS, PI3K-AKT pathways or TP53 with mutations of either ALK, ATM, APC, CDKN2A, ERBB2, RET or SMAD4, including mutations not yet described in thyroid tumors. Potential targeted genes were affected: mutations in ATM gene in 4 cases (4.3%), in ERBB2 in 1 case (1.1%), in MET in 1 case (1.1%) and in ALK in 1 case (1.1%). TERT promoter alteration was found in 53 cases (54.0%) including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in our panel of targeted genes.
CONCLUSION: Our study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, involving many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.

PMID: 28351340 [PubMed - as supplied by publisher]

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