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首页> 美国卫生研究院文献>International Journal of Clinical and Experimental Pathology >Identifying a wide range of actionable variants using capture-based ultra-deep targeted sequencing in treatment-naive patients with primary lung adenocarcinoma
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Identifying a wide range of actionable variants using capture-based ultra-deep targeted sequencing in treatment-naive patients with primary lung adenocarcinoma

机译：在未接受治疗的原发性肺腺癌患者中使用基于捕获的超深度靶向测序来鉴定各种可行的变异

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Precision medicine requires accurate multi-gene clinical diagnostics. In current clinical practice, the minimum confidence threshold for variant calling of targeted next-generation sequencing (NGS) on surgical specimens is set to 2%-5%. However, few studies have been conducted to identify a wide range of actionable variants using capture-based ultra-deep targeted sequencing, which has limit of detection (LOD) of 1%. The AmoyDx® Essential NGS panel for capture-based ultra-deep targeted sequencing (dual-indexed sequencing adapters with UMIs) was performed on 372 surgical specimens obtained from treatment-naive patients with primary lung adenocarcinoma, to detect actionable somatic driver mutations associated with each patient. Single-nucleotide variants, insertion/deletion events, and rearrangements were reported. Amplification-refractory mutation system (ARMS) assay and fluorescence in situ hybridization (FISH) were performed for the validation of hotspot mutations in EGFR and ALK, ROS1, and RET fusions. Potentially actionable variants were identified in 80.5% (352/437) of the nonsynonymous variants that were able to be sequenced, and were most commonly found in EGFR mutations (59.7%, 261/437), followed by KRAS mutations (5.5%, 24/437), PIK3CA mutations (3.7%, 16/437), ALK rearrangements (3.4%, 15/437), BRAF mutations (2.7%, 12/437), ERBB2 mutations (2.5%, 11/437), and RET rearrangements (2.3%, 10/437). A total of 7.2% (28/372) of the samples had multiple actionable mutations. Among the 93 triple-negative cases, which did not harbor mutations in EGFR, KRAS, or BRAF, gene fusions were detected in 26 cases (28%). Of the 328 samples, concordance of EGFR between the ARMS assay and NGS was observed in 318 samples (97.0%), and among 32 samples, concordance between ARMS/FISH test and NGS for ALK/ROS1/RET fusion genes was observed in 30 samples (93.8%). Here, we demonstrated that the capture-based ultra-deep targeted sequencing method, which has a LOD of 1% to profile a wide range of actionable variants in surgical specimens of treatment-naive lung adenocarcinoma patients, highlights the need for treatment-naive patients to undergo genomic profiling.
机译：精密医学需要准确的多基因临床诊断。在当前的临床实践中，将针对外科标本的靶向下一代测序（NGS）的变异调用的最小置信度阈值设置为2％-5％。但是，很少进行研究来使用基于捕获的超深靶向测序来鉴定多种可操作的变异体，其检测限（LOD）为1％。在从未接受过治疗的原发性肺腺癌患者中获得的372个手术标本上，进行了基于捕获的超深靶向测序（带有UMI的双索引测序适配器）的AmoyDx®Essential NGS面板，以检测与每种相关的可操作的体细胞驱动突变患者。报告了单核苷酸变体，插入/缺失事件和重排。进行了扩增-难治性突变系统（ARMS）分析和荧光原位杂交（FISH），以验证EGFR和ALK，ROS1和RET融合物中的热点突变。在80.5％（352/437）能够测序的非同义变体中鉴定出潜在可操作的变体，最常见的是EGFR突变（59.7％，261/437），其次是KRAS突变（5.5％，24 / 437），PIK3CA突变（3.7％，16/437），ALK重排（3.4％，15/437），BRAF突变（2.7％，12/437），ERBB2突变（2.5％，11/437）和RET重排（2.3％，10/437）。共有7.2％（28/372）的样本具有多个可操作的突变。在93例三阴性阴性病例中，它们没有EGFR，KRAS或BRAF突变，其中26例（28％）检测到基因融合。在328个样本中，有318个样本（97.0％）观察到EGFR在ARMS分析与NGS之间的一致性，在32个样本中，在30个样本中观察到了ARMS / FISH测试与NGS在ALK / ROS1 / RET融合基因之间的一致性。 （93.8％）。在这里，我们证明了基于捕获的超深度靶向测序方法的LOD为1％，可在未接受过治疗的肺腺癌患者的手术标本中分析多种可操作的变异，这突出表明了对未接受过治疗的肺腺癌患者的需求进行基因组分析。

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