Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches.
Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches.
复制标题
DOI：
10.1158/1078-0432.ccr-14-2683
复制
发表时间：
2015-08-15
期刊：
影响因子：
--
通讯作者：
Rizvi NA
中科院分区：
文献类型：
--
作者：
Drilon A;Wang L;Arcila ME;Balasubramanian S;Greenbowe JR;Ross JS;Stephens P;Lipson D;Miller VA;Kris MG;Ladanyi M;Rizvi NA
与使用多种非NGS测试的谱分析相比，基于混合捕获的下一代测序（NGS）作为临床测试，使用更少的组织来识别更多临床相关的基因组改变。我们开始通过这种方法确定肿瘤中这种基因组改变的频率，之前广泛的非ngs测试没有产生可靶向的驱动改变。我们招募了吸烟史≤15包年的肺腺癌患者，他们的肿瘤先前通过多种非ngs方法在11个基因（EGFR、ERBB2、KRAS、NRAS、BRAF、MAP2K1、PIK3CA和AKT1突变，以及涉及ALK、ROS1和RET的融合基因）的改变中检测为“阴性”。我们对287个癌症相关基因的编码外显子和19个重排基因的47个内含子进行了杂交捕获，并对这些基因进行了深度、均匀的测序。基于NCCN指南的靶向药物可操作的基因组改变有26% （8/31:EGFR G719A, BRAF V600E, SOCS5-ALK, CLIP4-ALK, CD74-ROS1, KIF5B-RET [n=2], CCDC6-RET）。这些患者中有7人接受了靶向治疗或有可能接受靶向治疗。在临床试验中，使用该方法的全面基因组分析还发现了另外39%（12/31）的靶向药物的基因组改变。广泛的、基于混合捕获的NGS在65% （95% CI 48-82%）从不吸烟或轻度吸烟的肺癌患者的肿瘤中发现了可操作的基因组改变，早期广泛的非NGS检测认为没有可靶向的基因组改变。这些发现支持使用这种方法作为比非ngs检测更全面和有效的策略来进行肺腺癌的一线分析。
Broad, hybrid capture-based next-generation sequencing (NGS), as a clinical test, uses less tissue to identify more clinically relevant genomic alterations compared to profiling with multiple non-NGS tests. We set out to determine the frequency of such genomic alterations via this approach in tumors where previous extensive non-NGS testing had not yielded a targetable driver alteration. We enrolled lung adenocarcinoma patients with a ≤15 pack-year smoking history whose tumors previously tested “negative” for alterations in 11 genes (mutations in EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1, and fusions involving ALK, ROS1, and RET) via multiple non-NGS methods. We performed hybridization capture of the coding exons of 287 cancer-related genes and 47 introns of 19 frequently rearranged genes and sequenced these to deep, uniform coverage. Actionable genomic alterations with a targeted agent based on NCCN guidelines were identified in 26% (8/31: EGFR G719A, BRAF V600E, SOCS5-ALK, CLIP4-ALK, CD74-ROS1, KIF5B-RET [n=2], CCDC6-RET). 7 of these patients either received or are candidates for targeted therapy. Comprehensive genomic profiling using this method also identified a genomic alteration with a targeted agent available on a clinical trial in an additional 39% (12/31). Broad, hybrid capture-based NGS identified actionable genomic alterations in 65% (95% CI 48–82%) of tumors from never or light smokers with lung cancers deemed without targetable genomic alterations by earlier extensive non-NGS testing. These findings support first-line profiling of lung adenocarcinomas using this approach as a more comprehensive and efficient strategy compared to non-NGS testing.