A subgroup of anaplastic thyroid carcinomas harbors MET alterations with potential therapeutic options

Abstract

Anaplastic thyroid carcinoma (ATC) is a rare but biologically aggressive thyroid cancer with fatal clinical outcome and limited therapeutic options. Molecular studies of ATCs have described several genetic alterations leading to FDA approval of inhibitor therapy targeting BRAFV600E, NTRK, ALK and RET. MET alterations have been described in single cases, which have not yet led to approval for inhibitor therapy, although approval for these alterations in other tumors, such as lung cancer, already exist. Aim of this study was to provide an overview of MET alterations in ATC, highlighting their potential therapeutic relevance. In this study, a total of 28 ATCs were examined using MET immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and both RNA- and DNA-based next-generation sequencing. Molecular findings were correlated with tumor morphology as well as clinical follow-up data. Three ATC samples (10 %) revealed MET alterations, namely top-level gene amplification (defined by an average gene count ≥10.0) and ETV6-MET fusion. Concomitant MET protein overexpression was demonstrated by IHC. One case without a detectable MET alteration showed IHC-positivity in > 50 % of the tumor cells with strong staining intensity. Two top-level amplified samples expressed the same chimeric CAPZA2–MET fusion transcript, which we interpret as a biological byproduct rather than a true molecular driver. DNA sequencing did not reveal any activating MET mutations including exon 14 skipping. MET alterations were here mutually exclusive with driver mutations in BRAF, RAS, and PIK3CA, but co-occurred with TP53 mutations and TERT promoter mutations. MET alterations in ATC have been poorly described to date. Herein, we present the first structured evaluation of a series of ATCs focusing on MET gene alterations, including gene amplification, immunohistochemical expression, and gene fusions. Our results confirm that MET top-level amplifications (detected by fluorescence in situ hybridization, FISH) and MET gene fusions (detected by RNA-based NGS) occur in a subgroup of ATCs. As these alterations are druggable in other cancers, early molecular testing may identify MET-positive ATCs eligible for anti-MET therapies in clinical trials. We recommend RNA-based sequencing and FISH as biomarker assays to identify MET alterations.