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Molecular Profile of Advanced Thyroid Carcinomas by Next-Generation Sequencing: Characterizing tumors beyond diagnosis for targeted therapy
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-04-25 , DOI: 10.1158/1535-7163.mct-17-0871
Hui Chen 1 , Rajyalakshmi Luthra 2 , Mark J. Routbort 2 , Keyur P. Patel 2 , Maria E. Cabanillas 3 , Russell R. Broaddus 1 , Michelle D. Williams 1
Affiliation  

Next-generation sequencing (NGS) for molecular diagnostics allows simultaneous testing of activating oncogenes and tumor suppressor mutations in multiple signal pathways. Extended mutational profiling of advanced thyroid cancers may enhance considerations for targeted therapies. We analyzed clinically derived molecular profiling of 216 patients with advanced thyroid carcinoma using NGS (Ion Torrent Personal Genome Machine) from April 2012 to February 2014. We examined substitutions and small indels in 46 or 50 cancer-related genes using Ampliseq Cancer Hotspot panel in respect to tumor diagnosis and clinical correlations. Mutations were common in advanced thyroid carcinomas 154 (71%) predominately in targetable MAPK pathway (146/216, 68%), and several PI3K/AKT pathway (8, 4%; six as comutations). BRAF V600E mutation associated with papillary (94/139, 68%), poorly differentiated (4/39, 10%), and anaplastic (3/12, 25%) carcinomas. NRAS mutations occurred in follicular (5/12, 42%) and poorly differentiated thyroid carcinoma (12/39, 31%). Tumor suppressor mutations (16, 7%) occurred predominantly in TP53 in Hurthle cell (2/5, 40%, the only mutation), in anaplastic (3/12, 25%) and poorly differentiated thyroid carcinoma (4/39, 10%) some as comutations and in papillary thyroid carcinoma (5/139, 4%) always a comutation. Kaplan–Meier analysis of patients with poorly differentiated thyroid carcinoma containing activating mutations who received targeted therapeutics showed improved survival compared to similarly treated patients without mutations in targetable pathways (P = 0.02). In conclusion, MAPK pathway is the predominant target for therapy in advance thyroid carcinomas; adding NGS enables the identification of comutations associated with resistance (PI3K/AKT). Within poorly differentiated thyroid carcinoma, the molecular profile may hold prognostic value in the era of targeted therapy. Mol Cancer Ther; 17(7); 1575–84. ©2018 AACR.

中文翻译:

通过下一代测序分析晚期甲状腺癌的分子特征:表征肿瘤以进行靶向治疗的诊断

用于分子诊断的新一代测序 (NGS) 允许同时测试多个信号通路中的激活癌基因和肿瘤抑制突变。晚期甲状腺癌的扩展突变分析可能会增加对靶向治疗的考虑。2012 年 4 月至 2014 年 2 月,我们使用 NGS(离子激流个人基因组机器)分析了 216 名晚期甲状腺癌患者的临床衍生分子谱。肿瘤诊断和临床相关性。突变在晚期甲状腺癌中很常见 154 (71%),主要是靶向 MAPK 通路 (146/216, 68%) 和几种 PI3K/AKT 通路 (8, 4%;6 个作为突变)。BRAF V600E 突变与乳头状癌 (94/139, 68%)、低分化癌 (4/39, 10%) 和间变性 (3/12, 25%) 癌相关。NRAS 突变发生在滤泡癌 (5/12, 42%) 和低分化甲状腺癌 (12/39, 31%) 中。肿瘤抑制突变 (16, 7%) 主要发生在 Hurthle 细胞的 TP53 (2/5, 40%, 唯一突变)、间变性 (3/12, 25%) 和低分化甲状腺癌 (4/39, 10 %) 一些作为 comutations 和在乳头状甲状腺癌 (5/139, 4%) 总是一个 coutation。对接受靶向治疗的含有激活突变的低分化甲状腺癌患者的 Kaplan-Meier 分析显示,与没有靶向通路突变的类似治疗患者相比,生存率提高(P = 0.02)。综上所述,MAPK 通路是晚期甲状腺癌治疗的主要靶点;添加 NGS 可以识别与耐药性 (PI3K/AKT) 相关的突变。在低分化甲状腺癌中,分子特征可能在靶向治疗时代具有预后价值。摩尔癌症治疗; 17(7); 1575-84 年。©2018 AACR。
更新日期:2018-04-25
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