NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma
NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma
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DOI：
10.18632/oncotarget.17300
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发表时间：
2017-06-27
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影响因子：
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通讯作者：
Schmid, Kurt Werner
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文献类型：
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作者：
Tiedje, Vera;Ting, Saskia;Schmid, Kurt Werner
背景：间变性甲状腺癌（ATC）是最具侵袭性的癌症之一，在常规放化疗治疗时没有一致的生存益处。针对ATC“癌基因成瘾”的方法正在被越来越多地探索，并在单例研究中报告了初步有希望的结果。目的：确定ATC大队列中已知甲状腺癌基因突变的发生率和靶向治疗可修改的信号通路。结果：118例ATC（男57例，女61例）共发现165个突变。参与MAPK/ERK和PI3K通路的基因（BRAF 11.0%, HRAS 4.2%, KRAS 7.6%, NRAS 7.6%, PI3KCA 11.8%）在33%中发生改变。11%的靶受体酪氨酸激酶发生突变。最常见的基因改变是TERT(86/118)（73%）和p53(65/118)（55%）。分析ALK、KIT、MET和mTOR均未发现突变。材料和方法：使用MiSeq （Illumina）和CLC Cancer Research Workbench （CLCbio; Qiagen）对118 ATC的FFPE样本进行下一代测序（NGS），用于突变分析：ALK、BRAF、CDKN2A、EGFR、ERBB2、HRAS、KIT、KRAS、MET、mTOR、NRAS、PDGFRA、PI3KCA、p53、RB1、RET和TSC2。采用Sanger测序检测TERT启动子突变。结论：据我们所知，这是分析ATC靶向治疗突变的最大研究。我们发现33%的ATC在可靶向治疗的通路中携带突变。由于目前对ATC的常规治疗主要无效，因此建议对ATC进行分子筛选以进行靶向治疗。
Context: Anaplastic thyroid carcinoma (ATC) represents one of the most aggressive carcinomas with no consistent survival benefit when treated with conventional radiochemotherapy. Approaches targeting "oncogene addiction" of ATC are increasingly explored and first promising results have been reported in single case studies. Objective: To determine the prevalence of mutations in known thyroid oncogenes and signalling pathways amendable to targeted therapy in a large cohort of ATC.Results: In 118 ATC (57 male/ 61 female) a total of 165 mutations were found. Genes involved in the MAPK/ERK and PI3K pathway (BRAF 11.0%, HRAS 4.2%, KRAS 7.6%, NRAS 7.6%, PI3KCA 11.8%) were altered in 33%. Targetable receptor tyrosine kinases were mutated in 11%. The most frequently altered genes were TERT in 86/118 (73%) and p53 in 65/118 (55%) cases. No mutations were found analysing ALK, KIT, MET and mTOR.Materials and Methods: Next generation sequencing (NGS) was performed in FFPE samples from 118 ATC using MiSeq (Illumina) and CLC Cancer Research Workbench (CLCbio; Qiagen) for mutation analysis in: ALK, BRAF, CDKN2A, EGFR, ERBB2, HRAS, KIT, KRAS, MET, mTOR, NRAS, PDGFRA, PI3KCA, p53, RB1, RET and TSC2. Sanger sequencing was used to detect TERT promotor mutations.Conclusions: To our knowledge this is the largest study analysing mutations for targeted therapy of ATC. We found that 33% of ATC harbour mutations in pathways amendable to targeted therapy. Molecular screening in ATC is suggested for targeted therapies since current conventional treatment for ATC proved mainly futile.