脑脊液游离 DNA 作为液体活检在 ALK 重排 NSCLC 脑膜转移中的临床应用
Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC.
机构信息
Guangdong General Hospital, School of Medicine, South China University of Technology, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
出版信息
J Thorac Oncol. 2019 May;14(5):924-932. doi: 10.1016/j.jtho.2019.01.007. Epub 2019 Jan 17.
INTRODUCTION
Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene-mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce.
METHODS
Patients with lung cancer with ALK rearrangement were screened from September 2011 to February 2018 at our institute. CSF and paired plasma were tested by next-generation sequencing.
RESULTS
LMs were diagnosed in 30 (10.3%) of 291 patients with ALK-rearranged lung cancer. A total of 11 paired CSF and plasma samples tested by next-generation sequencing were analyzed. Driver genes were detected in 81.8% of the CSF samples (9 of 11) and 45.5% of the plasma samples (5 of 11) (p = 0.183). The maximum allelic fractions were all higher in CSF than in plasma (p = 0.009). ALK and tumor protein p53 gene (TP53) were the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutations were identified in CSF after resistance to alectinib. Multiple copy number variants were mainly found in CSF, including in EGFR, cyclin D1 gene (CCND1), fibroblast growth factor 3 gene (FGF3), and fibroblast growth factor 4 gene (FGF4). Also found were v-myc avian myelocytomatosis viral oncogene homolog gene (MYC) copy number gains and TP53 and cyclin dependent kinase inhibitor 2A gene (CDKN2A) copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF could be used to monitor disease development of LM and longitudinally monitor tumor response.
CONCLUSION
Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM.
简介
脑膜转移（LM）在非小细胞肺癌（NSCLC）中预示着预后不良。在驱动基因突变的患者中，LM 更为常见，而脑脊液（CSF）无细胞 DNA 显示出 EGFR 突变 LM 中独特的遗传特征。然而，ALK 受体酪氨酸激酶基因（ALK）重排的 NSCLC 伴 LM 患者的研究较少。
方法
我们从 2011 年 9 月至 2018 年 2 月在我院筛选出具有 ALK 重排的肺癌患者。通过下一代测序检测 CSF 和配对血浆。
结果
在 291 例 ALK 重排的肺癌患者中，诊断出 30 例（10.3%）LM。分析了 11 对通过下一代测序检测的 CSF 和血浆样本。CSF 样本中检测到驱动基因的占 81.8%（9/11），血浆样本中检测到驱动基因的占 45.5%（5/11）（p=0.183）。最大等位基因分数均高于血浆（p=0.009）。CSF 中最常突变的基因是 ALK 和肿瘤蛋白 p53 基因（TP53）。在对艾乐替尼耐药后，在 CSF 中检测到了 ALK G1202R 和 C1156F 突变。主要在 CSF 中发现多个拷贝数变异，包括 EGFR、细胞周期蛋白 D1 基因（CCND1）、成纤维细胞生长因子 3 基因（FGF3）和成纤维细胞生长因子 4 基因（FGF4）。还发现 v-myc 禽髓细胞瘤病毒癌基因同源物基因（MYC）拷贝数增加和细胞周期蛋白依赖性激酶抑制剂 2A 基因（CDKN2A）拷贝数缺失。布加替尼似乎能有效控制 LM。有一例表明 CSF 可用于监测 LM 的疾病进展，并纵向监测肿瘤对 ALK 重排的 NSCLC 伴 LM 患者的反应。
结论
CSF 的液体活检比血浆的液体活检更能灵敏地检测到可靶向的改变，在进展时描绘耐药机制，并监测 ALK 重排的 NSCLC 伴 LM 患者的肿瘤反应。因此，CSF 作为 LM 液体活检的媒介可能很有前途。
Zotero 插件