Department of Medicine, Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, Moores Cancer Center, San Diego, California.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2017 Apr 15;23(8):1988-1997. doi: 10.1158/1078-0432.CCR-16-1679. Epub 2016 Sep 28.
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 aberrations across multiple cancers may facilitate clinical trial development targeting We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels. Among diverse cancers, 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 ] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to anomalies [81.8% (72/88)], with the most common being in -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)]. 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 () and medullary thyroid carcinoma ( M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown. 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 anomalies will require customized combination strategies. .
遗传序列中编码酪氨酸激酶受体 RET 的突变导致致癌信号，可通过抗 RET 多激酶抑制剂进行靶向治疗。了解多种癌症中基因序列的全面基因组改变情况，可能有助于开发针对这些改变的临床试验。我们使用经过 CLIA 认证的靶向下一代测序，对 4871 名患有不同恶性肿瘤的患者进行了 182 或 236 个基因组合的分子谱分析，以确定是否存在异常。在不同的癌症中，有 88 例患者（1.8%（88/4871））存在异常，其中最常见的是突变（38.6%（34/88）），其次是融合（30.7%（27/88），包括一个新的）和扩增（25%（22/88））。除了异常外，大多数患者还存在共存的异常（81.8%（72/88）），最常见的是与 RET 相关的基因（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 效应物（22.7%（20/88））或其他酪氨酸激酶家族（21.6%（19/88））。融合与 MAPK 信号通路改变是相互排斥的。所有 72 名存在共存异常的患者都有独特的基因组谱，大多数（98.6%（71/72））都存在潜在的可靶向共存异常，这些异常可以使用 FDA 批准的药物或研究性药物进行治疗。两例患有肺（）和甲状腺髓样癌（M918T）的患者对包含凡德他尼（一种多激酶 RET 抑制剂）的治疗方案有反应，这两例患者的治疗方案也被展示出来。RET 异常在不同癌症中的发生率为 1.8%，大多数病例存在可治疗的、尽管是不同的共存改变。本报告提示，要对存在 RET 异常的患者进行最佳靶向治疗，可能需要采用定制的联合治疗策略。
