Bonhomme Benjamin, Godbert Yann, Perot Gaelle, Al Ghuzlan Abir, Bardet Stéphane, Belleannée Geneviève, Crinière Lise, Do Cao Christine, Fouilloux Geneviève, Guyetant Serge, Kelly Antony, Leboulleux Sophie, Buffet Camille, Leteurtre Emmanuelle, Michels Jean-Jacques, Tissier Frédérique, Toubert Marie-Elisabeth, Wassef Michel, Pinard Clémence, Hostein Isabelle, Soubeyran Isabelle
1 Department of Biopathology, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
2 Nuclear Medicine and Thyroid Oncology Unit, Molecular Pathology Unit, Institut Bergonié , Bordeaux, France .
Thyroid. 2017 May;27(5):682-692. doi: 10.1089/thy.2016.0254.
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.
间变性甲状腺癌（ATC）是一种罕见肿瘤，其致癌分子机制尚不明确，治疗选择有限，导致预后较差。本回顾性研究的目的是确定间变性淋巴瘤激酶（ALK）易位的频率，并确定ATC的突变谱，包括端粒酶逆转录酶（TERT）启动子突变。
从法国全国难治性甲状腺肿瘤管理网络的10个中心收集了144例ATC病例。在组织微阵列上进行ALK重排的荧光原位杂交分析。还使用下一代测序筛选了一组50个基因，并使用桑格测序法检测TERT启动子突变。
90例（62.5%）病例的荧光原位杂交结果可解读。1例（1.1%）病例ALK重排呈阳性，处于临界阈值（15%阳性细胞）。94例（65.3%）病例的下一代测序结果可解读，98例（68.1%）病例的桑格测序（TERT）结果可解读。共鉴定出210个突变（内含子和外显子）。TP53改变最为常见（54.4%）。43%的病例存在（H-K-N）RAS基因突变，13.8%存在BRAF基因突变（主要是p.V600E），17%存在PI3K-AKT途径突变，6.4%同时存在RAS和PI3K途径突变，4.3%同时存在TP53和PTEN突变。近10%的病例未显示RAS、PI3K-AKT途径或TP53突变，但存在ALK、ATM、APC、CDKN2A、ERBB2、RET或SMAD4突变，包括甲状腺肿瘤中尚未描述的突变。编码潜在可靶向治疗靶点的基因包括：4例（4.3%）病例存在ATM基因突变，1例（1.1%）病例存在ERBB2基因突变，1例（1.1%）病例存在MET基因突变，1例（1.1%）病例存在ALK基因突变。53例（54.0%）病例发现TERT启动子改变，包括43例C228T和10例C250T突变。我们的3例病例在具有治疗意义的基因面板中未发现突变。
本研究证实ATC中的ALK重排罕见，且ATC的突变谱具有异质性，许多基因参与滤泡上皮细胞去分化过程。这可能解释了迄今为止所测试的靶向治疗方案效果有限的原因。
