Department of Thyroid and Parathyroid Surgery, Laboratory of thyroid and parathyroid disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.
J Clin Endocrinol Metab. 2021 Mar 25;106(4):988-998. doi: 10.1210/clinem/dgab014.
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.
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.
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.
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.
间变性甲状腺癌（ATC）是一种罕见但致命的恶性肿瘤，针对中国患者的 ATC 基因组特征，目前仅有少数系统性研究。
回顾性分析了 2010 年至 2020 年在华西医院就诊的 54 例 ATC 患者，其中 29 例有可用样本的患者进行了全外显子组测序（WES）。统计评估了基因组改变与临床特征之间的关联。
整个队列的中位总生存期为 3.0 个月，受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%）。尽管这些突变在以前的研究中已有报道，但在突变频率方面表现出种族特异性。此外，还鉴定出了几个新的显著突变基因，包括 RBM15（17%）、NOTCH2NL（14%）、CTNNA3（10%）和 KATNAL2（10%）。基于 WES 的拷贝数改变分析还揭示了 NOTCH2NL 的高频获得（41%），导致其表达增加。基因突变和拷贝数改变在磷脂酰肌醇 3-激酶/AKT/雷帕霉素（mTOR）、NOTCH 和 WNT 途径中富集。
本研究揭示了中国患者 ATC 的共享和种族特异性基因组特征，并表明 NOTCH2NL 可能作为 ATC 肿瘤发生的新候选驱动基因。
