Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS
Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS
复制标题
DOI：
10.1210/jc.2012-2703
复制
发表时间：
2013-02-01
影响因子：
5.8
通讯作者：
Ball, Douglas W.
中科院分区：
文献类型：
--
作者：
Agrawal, Nishant;Jiao, Yuchen;Ball, Douglas W.
内容：甲状腺髓样癌（MTC）是一种罕见的甲状腺癌，可偶发发生或作为遗传综合征的一部分。目的：为了探讨MTC的遗传起源，我们对17例散发性MTC中约21，000个基因的蛋白编码外显子进行了测序。我们对17个散发性MTCs的外显子组进行了测序，并在一个40个独立队列中验证了所有复发突变基因和其他感兴趣基因的频率。MTCs包括散发性和遗传性MTC.Results：我们发现了305个高置信度的突变，在17个散发性MTCs的发现阶段，或约17.9体细胞突变每个肿瘤。RET、HRAS和KRAS基因突变被确定为MTC的主要驱动突变。所有其他额外的体细胞突变，包括剪接体和DNA修复途径的突变，在其他肿瘤中不会复发。没有RET，HRAS，或KRAS突变的肿瘤似乎有显着较少的突变整体在蛋白编码exons.Conclusions：大约90%的MTCs有互斥的突变RET，HRAS和KRAS，这表明RET和RAS是主要的驱动途径在MTC。在MTC外显子组中观察到总体相对较少的突变，并且除了RET、HRAS和KRAS之外没有常见的复发性驱动突变。（临床内分泌代谢杂志98：E364-E369，2013）
Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome.Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs.Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC.Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons.Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome. (J Clin Endocrinol Metab 98: E364-E369, 2013)