Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer
Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer
复制标题
中国甲状腺未分化癌患者中新的复发性改变基因
DOI：
10.1210/clinem/dgab014
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发表时间：
2021-01-11
影响因子：
5.8
通讯作者：
Luo, Han
中科院分区：
文献类型：
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作者：
Zhang, Lingyun;Ren, Zhixiang;Luo, Han
背景：未分化甲状腺癌（ATC）是一种罕见但致命的恶性肿瘤，在中国患者中很少有对ATC基因组图谱的系统性研究。
方法：对2010年至2020年华西医院的54例ATC患者进行回顾性分析，同时对29例有可用样本的患者进行全外显子组测序（WES）。对基因组改变与临床特征之间的关联进行统计学评估。
结果：整个队列的中位总生存期为3.0个月，受到多种临床特征的影响，包括年龄、肿瘤大小和不同的治疗策略。在WES队列中，共检测到797个非同义突变；最常发生改变的基因是TP53（48%）、BRAF（24%）、PIK3CA（24%）和TERT启动子（21%）。尽管这些突变在先前的研究中已有充分报道，但在突变频率方面表现出种族特异性。此外，还鉴定出几个新的显著突变基因，包括RBM15（17%）、NOTCH2NL（14%）、CTNNA3（10%）和KATNAL2（10%）。基于WES的拷贝数变异分析还显示NOTCH2NL高频扩增（41%），导致其表达增加。基因突变和拷贝数变异在磷脂酰肌醇3 - 激酶/AKT/雷帕霉素靶蛋白（mTOR）、NOTCH和WNT通路中富集。
结论：本研究揭示了中国患者中ATC共有的和具有种族特异性的基因组图谱，并表明NOTCH2NL可能是ATC肿瘤发生的一个新的候选驱动基因。
Background: Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy, and few systematic investigations on genomic profiles of ATC have been performed in Chinese patients.Methods: Fifty-four ATC patients in West China Hospital between 2010 to 2020 were retrospectively analyzed, while 29 patients with available samples were sequenced by whole-exome sequencing (WES). The associations between genomic alterations and clinical characteristics were statistically evaluated.Results: The median overall survival was 3.0 months in the entire cohort, which was impacted by multiple clinical features, including age, tumor size, and different treatment strategies. In the WES cohort, totally 797 nonsilent mutations were detected; the most frequently altered genes were TP53 (48%), BRAF (24%), PIK3CA (24%), and TERT promoter (21%). Although these mutations have been well-reported in previous studies, ethnic specificity was exhibited in terms of mutation frequency. Moreover, several novel significantly mutated genes were identified including RBM15 (17%), NOTCH2NL (14%), CTNNA3 (10%), and KATNAL2 (10%). WES-based copy number alteration analysis also revealed a high frequent gain of NOTCH2NL (41%), which induced its increased expression. Gene mutations and copy number alterations were enriched in phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (mTOR), NOTCH, and WNT pathways.Conclusions: This study reveals shared and ethnicity-specific genomic profiles of ATC in Chinese patients and suggests NOTCH2NL may act as a novel candidate driver gene for ATC tumorigenesis.