The Second Hospital of Dalian Medical University, Dalian, China.
Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Cancer Med. 2019 Sep;8(12):5673-5686. doi: 10.1002/cam4.2458. Epub 2019 Aug 1.
Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer-associated genes across varying sample sites in lung cancer patients.
Targeted deep sequencing for 48 tumor-related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin-fixed paraffin-embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma.
Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV-dominated, CNV-dominated, and codominated groups.
Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.
靶向治疗基于特定的基因改变。已经使用了各种标本类型来确定基因改变，但尚未进行系统比较。在此，我们评估了 55 名肺癌患者的 153 个样本中选定的癌症相关基因的改变，这些样本来自六个不同的样本部位。
对 55 名肺癌患者的 153 个样本应用了针对 48 个肿瘤相关基因的靶向深度测序，这些样本来自六个来源：福尔马林固定石蜡包埋（FFPE）肿瘤组织、胸腔积液上清液（PES）和胸腔积液细胞沉淀物（PEC）、白细胞（WBC）、口腔上皮细胞（OEC）和血浆。
96%（53/55）的患者和 83%（40/48）的选定基因中检测到突变。每种样本类型都表现出独特的突变模式。如预期的那样，TP53 是受影响最严重的序列（54.5%的患者），但紧随其后的是 NOTCH1（所有样本类型的 36%）。EGFR 在患者样本中的改变频率为 32.7%，KRAS 为 10.9%。这种高 EGFR/低 KRAS 频率与其他亚洲起源的 TCGA 队列一致，但与白种人群不同，白种人群中 KRAS 是更为主要的突变。此外，66%（31/47）的 PEC 样本在至少一个基因中存在拷贝数变异（CNV）。与大多数基因的同时缺失和获得不同，NOTCH1 的缺失在 21%的患者中被发现，没有观察到获得。基于突变和 CNV 的相对流行程度，我们将肺癌患者分为单核苷酸变异（SNV）主导、CNV 主导和共同主导组。
我们的结果证实了以前的报告，即 EGFR 突变在中国肺癌患者中比 KRAS 更为常见。NOTCH1 基因改变比以前报道的更为常见，并揭示了 NOTCH1 修饰在肿瘤转移中的作用。此外，来自恶性胸腔积液细胞沉淀物的遗传物质可能是一种非侵入性的方法，可以识别 CNV 并参与治疗决策。
