Department of Lung Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, China; BGI Genomics, BGI-Shenzhen, Shenzhen, China.
Lung Cancer. 2019 Aug;134:108-116. doi: 10.1016/j.lungcan.2019.05.034. Epub 2019 May 31.
Circulating tumor DNA (ctDNA) testing in plasma in patients with non-small-cell lung cancer (NSCLC) has the potential to be a supplemental or surrogate tool for tissue biopsy. Detection of genomic abnormalities in ctDNA and their association with clinical characteristics in early-stage NSCLC need to be clarified.
Here, we comprehensively analyzed gene variations of 48 tumor tissues and 48 matched preoperative (pre-op) plasma and 25 postoperative (post-op) plasma from early-stage NSCLC patients using a targeted 546 genes capture-based next generation sequencing (NGS) assay.
In early-stage NSCLC, the average mutation allele frequency (MAF) in pre-op plasma ctDNA was lower than that in tissue DNA (tDNA). The concordant gene variations between pre-op ctDNA and tDNA were difficult to detect. However, we found the tissue- pre-op plasma concordant ctDNA mutation detection ratio in lung squamous cell carcinoma (LUSC) was much higher than that in lung adenocarcinoma (LUAD). We also established a LUSC-LUAD classification model by a least absolute shrinkage and selection operator (LASSO) based approach to help separate LUAD from LUSC based on ctDNA profiling. This model included 14 gene mutations and extracted an accuracy of 89.2% in the training set and 91.5% in the testing set. Correlation analysis showed tDNA-ctDNA concordant ratio was related to histologic subtype, gene mutations and tumor size in early-stage NSCLC.
This study suggests histology subtype and gene mutations could affect ctDNA detection in early-stage NSCLC. NGS-based ctDNA profile has the potential utility in LUSC-LUAD classification.
在非小细胞肺癌（NSCLC）患者的血浆中检测循环肿瘤 DNA（ctDNA）有可能成为组织活检的补充或替代工具。需要阐明 ctDNA 中基因组异常的检测及其与早期 NSCLC 临床特征的相关性。
在这里，我们使用靶向 546 个基因捕获的下一代测序（NGS）检测方法，全面分析了 48 例早期 NSCLC 患者的 48 例肿瘤组织和 48 例术前（术前）血浆以及 25 例术后（术后）血浆的基因变异。
在早期 NSCLC 中，术前血浆 ctDNA 的平均突变等位基因频率（MAF）低于组织 DNA（tDNA）。术前 ctDNA 与 tDNA 之间的一致基因变化难以检测到。然而，我们发现肺鳞癌（LUSC）组织-术前血浆一致 ctDNA 突变检测率明显高于肺腺癌（LUAD）。我们还通过最小绝对收缩和选择算子（LASSO）方法建立了一个 LUSC-LUAD 分类模型，以帮助根据 ctDNA 谱分离 LUAD 和 LUSC。该模型包括 14 个基因突变，在训练集和测试集中的准确率分别为 89.2%和 91.5%。相关性分析表明，tDNA-ctDNA 一致性比率与早期 NSCLC 的组织学亚型、基因突变和肿瘤大小有关。
本研究表明组织学亚型和基因突变可能影响早期 NSCLC 中的 ctDNA 检测。基于 NGS 的 ctDNA 谱在 LUSC-LUAD 分类中有潜在的应用价值。
