Theurer Sarah, Schildhaus Hans-Ulrich, Herold Thomas, Brandenburg Tim, Führer-Sakel Dagmar, Baba Hideo Andreas, Ingenwerth Marc, Borchert Sabrina
Institute of Pathology, University Hospital Essen and Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
Institute of Pathology Nordhessen, Kassel, Germany; Discovery Life Sciences, Kassel, Germany.
Pathol Res Pract. 2025 Nov;275:156240. doi: 10.1016/j.prp.2025.156240. Epub 2025 Sep 21.
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.
间变性甲状腺癌（ATC）是一种罕见但生物学行为侵袭性强的甲状腺癌，临床预后不良，治疗选择有限。对ATC的分子研究描述了几种基因改变，这使得针对BRAFV600E、NTRK、ALK和RET的抑制剂疗法获得了美国食品药品监督管理局（FDA）的批准。在个别病例中已发现MET改变，但尚未获批抑制剂疗法，尽管在其他肿瘤（如肺癌）中针对这些改变的疗法已获批准。本研究的目的是概述ATC中的MET改变，强调其潜在的治疗相关性。在本研究中，共使用MET免疫组织化学（IHC）、荧光原位杂交（FISH）以及基于RNA和DNA的二代测序对28例ATC进行了检测。分子研究结果与肿瘤形态以及临床随访数据相关联。3例ATC样本（10%）显示存在MET改变，即高水平基因扩增（定义为平均基因计数≥10.0）和ETV6-MET融合。免疫组织化学证实存在伴随的MET蛋白过表达。1例未检测到MET改变的病例在>50%的肿瘤细胞中显示免疫组织化学阳性，且染色强度较强。2例高水平扩增样本表达相同的嵌合CAPZA2-MET融合转录本，我们将其解释为一种生物学副产物而非真正的分子驱动因素。DNA测序未发现任何激活的MET突变，包括外显子14跳跃。在此，MET改变与BRAF、RAS和PIK3CA中的驱动突变相互排斥，但与TP53突变和TERT启动子突变同时出现。迄今为止，对ATC中MET改变的描述较少。在此，我们首次对一系列ATC进行了结构化评估，重点关注MET基因改变，包括基因扩增、免疫组织化学表达和基因融合。我们的结果证实，MET高水平扩增（通过荧光原位杂交，即FISH检测）和MET基因融合（通过基于RNA的二代测序检测）发生在一部分ATC中。由于这些改变在其他癌症中是可靶向治疗的，早期分子检测可能会识别出符合条件在临床试验中接受抗MET治疗的MET阳性ATC。我们推荐基于RNA的测序和FISH作为识别MET改变的生物标志物检测方法。
