Cai Jun, Jiang Huihui, Li Shuqing, Yan Xiaoxia, Wang Meng, Li Na, Zhu Cuimin, Dong Hui, Wang Dongjuan, Xu Yue, Xie Hui, Wu Shouxin, Lou Jingwei, Zhao Jiangman, Li Qingshan
Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, China.
Zhangjiang Center for Translational Medicine, Shanghai Biotecan Pharmaceuticals Co., Ltd., Shanghai, China.
Front Oncol. 2022 Feb 22;11:751106. doi: 10.3389/fonc.2021.751106. eCollection 2021.
Circulating tumor DNA (ctDNA) sequence analysis shows great potential in the management of non-small cell lung cancer (NSCLC) and the prediction of drug sensitivity or resistance in many cancers. Here, we drew and compared the somatic mutational profile using ctDNA and tumor tissue sequence analysis in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), and assess its potential clinical value.
In this study, 221 tumor tissues and 174 plasma samples from NSCLC patients were analyzed by hybridization capture-based next-generation sequencing (NGS) panel including 95 cancer-associated genes. Tumor response assessments were applied to 137 patients with advanced-stage (III and IV) NSCLC who first received targeted agents.
Twenty significantly mutated genes were identified such as , and . Among them, was the most frequently mutated gene and had a higher mutation probability in male (p = 0.00124) and smoking (p < 0.0001) patients. A total of 48.35% (191/395) of NSCLC patients possessed at least one actionable alteration according to the OncoKB database. Although the sensitivity of genomic profiling from ctDNA was lower than that from tumor tissue DNA, the mutational landscape of target genes from ctDNA is similar to that from tumor tissue DNA, which led to 61.22% (30/49) of mutational concordance in NSCLC. Additionally, the mutational concordance between tissue DNA and ctDNA in LUAD differs from that in LUSC, which is 63.83% versus 46.67%, indicating that NSCLC subtypes influence the specificity of mutation detection in plasma-derived ctDNA. Lastly, patients with and co-alterations showed similar responses to Gefitinib and Icotinib, and the co-occurring mutation was most likely to be a poor prognostic factor for patients receiving Gefitinib, indicating that the distributions and types of mutations may contribute to the efficacy and prognosis of molecular targeted therapy.
As a promising alternative for tumor genomic profiling, ctDNA analysis is more credible in LUAD than in LUSC. Genomic subtyping has strong potential in prognostication and therapeutic decision-making for NSCLC patients, which indicated the necessity for the utility of target NGS in guiding clinical management.
循环肿瘤DNA（ctDNA）序列分析在非小细胞肺癌（NSCLC）的管理以及多种癌症的药物敏感性或耐药性预测中显示出巨大潜力。在此，我们绘制并比较了肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）中使用ctDNA和肿瘤组织序列分析的体细胞突变图谱，并评估其潜在的临床价值。
在本研究中，通过基于杂交捕获的下一代测序（NGS）面板对来自NSCLC患者的221个肿瘤组织和174份血浆样本进行分析，该面板包括95个癌症相关基因。对137例首次接受靶向药物治疗的晚期（III期和IV期）NSCLC患者进行肿瘤反应评估。
鉴定出20个显著突变基因，如 ， 等。其中， 是最常突变的基因，在男性（p = 0.00124）和吸烟（p < 0.0001）患者中具有更高的突变概率。根据OncoKB数据库，共有48.35%（191/395）的NSCLC患者至少有一个可操作的改变。虽然ctDNA基因组分析的敏感性低于肿瘤组织DNA，但ctDNA中靶基因的突变图谱与肿瘤组织DNA相似，这导致NSCLC中61.22%（30/49）的突变一致性。此外，LUAD中组织DNA和ctDNA之间的突变一致性与LUSC不同，分别为63.83%和46.67%，表明NSCLC亚型影响血浆来源ctDNA中突变检测的特异性。最后， 和 共同改变的患者对吉非替尼和埃克替尼表现出相似的反应，同时发生的 突变最有可能是接受吉非替尼治疗患者的不良预后因素，表明 突变的分布和类型可能有助于分子靶向治疗的疗效和预后。
作为肿瘤基因组分析的一种有前景的替代方法，ctDNA分析在LUAD中比在LUSC中更可靠。基因组亚型在NSCLC患者的预后和治疗决策中具有强大潜力，这表明在指导临床管理中使用靶向NGS的必要性。
