RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients
RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients
复制标题
DOI：
10.1158/1078-0432.ccr-16-1679
复制
发表时间：
2017-04-15
影响因子：
11.5
通讯作者：
Kurzrock, Razelle
中科院分区：
文献类型：
--
作者：
Kato, Shumei;Subbiah, Vivek;Kurzrock, Razelle
目的：编码酪氨酸激酶受体RET的基因序列的异常导致可被抗RET多激酶抑制剂靶向的致癌信号传导。了解多种癌症中RET畸变的全面基因组景观可能有助于靶向RET的临床试验开发。实验设计：我们使用临床实验室改进修正案认证的182或236个基因组的靶向下一代测序，询问了4，871名患有不同恶性肿瘤的患者的分子组合中是否存在RET畸变。结果：在各种癌症中，RET畸变在88例中被确定[1.8%（88/4，871）]，突变是最常见的改变[38.6%（34/88）]，其次是融合[30.7%（27/88），包括新的SQSTM 1-RET]和扩增[25%（22/88）]。除了RET异常外，大多数患者还存在共存的畸变[81.8%（72/88）]，最常见的是TP53相关基因[59.1%（52/88）]、细胞周期相关基因[39.8%（35/88）]、PI3K信号通路[30.7%（27/88）]、MAPK效应子[22.7%（20/88）]，或其他酪氨酸激酶家族[21.6%（19/88）]。RET融合与MAPK信号通路的改变是相互排斥的。所有72例存在共畸变的患者均具有不同的基因组组合，大多数[98.6%（71/72）]存在FDA批准或试验药物的潜在靶向共畸变。两例肺（KIF5B-RET）和甲状腺髓样癌（RET M918T），响应凡德他尼（多激酶RET抑制剂）-含regimen showed. Conclusions：RET畸变见于1.8%的不同癌症，大多数情况下窝藏可操作的，虽然不同的，共存的变化。目前的报告表明，RET异常患者的最佳靶向治疗需要定制的组合策略。(C)2016年AACR。
Purpose: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RET.Experimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.Results: Among diverse cancers, RET aberrations were identified in 88 cases [1.8% (88/4, 871)], with mutations being the most common alteration [38.6% (34/88)], followed by fusions [30.7% (27/88), including a novel SQSTM1-RET] and amplifications [25%(22/88)]. Most patients had coexisting aberrations in addition to RET anomalies [81.8% (72/88)], with the most common being in TP53-associated genes [59.1% 52/88)], cell cycle-associated genes [39.8% (35/88)], the PI3K signaling pathway [30.7% (27/88)], MAPK effectors [22.7% (20/88)], or other tyrosine kinase families [21.6% (19/88)]. RET fusions were mutually exclusive with MAPK signaling pathway alterations. All 72 patients harboring coaberrations had distinct genomic portfolios, and most [98.6% (71/72)] had potentially targetable coaberrations with either an FDA-approved or an investigational agent. Two cases with lung (KIF5B-RET) and medullary thyroid carcinoma (RET M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown.Conclusions: RET aberrations were seen in 1.8% of diverse cancers, with most cases harboring actionable, albeit distinct, coexisting alterations. The current report suggests that optimal targeting of patients with RET anomalies will require customized combination strategies. (C) 2016 AACR.