脑脊液游离 DNA 中的独特基因突变谱在 EGFR 突变型非小细胞肺癌脑膜转移中的作用：一种新的液体活检方法。
Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy.
机构信息
Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cance, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China.
Burning Rock Biotech, Guangzhou, China.
出版信息
Ann Oncol. 2018 Apr 1;29(4):945-952. doi: 10.1093/annonc/mdy009.
BACKGROUND
Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
PATIENTS AND METHODS
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
RESULTS
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P < 0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P = 0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CONCLUSION
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.
背景
表皮生长因子受体 (EGFR) 突变的非小细胞肺癌 (NSCLC) 更易发生脑膜转移 (LM)。由于脑膜病变的检测手段有限，本研究旨在探索脑脊液 (CSF) 作为 LM 患者液体活检来源的潜在作用。
方法
采用下一代测序技术对 LM 伴 NSCLC 的原发肿瘤、CSF 和血浆进行检测。共对 45 例疑似 LM 的患者进行腰椎穿刺，对确诊为 LM 且存在 EGFR 突变的患者进行入组。
结果
该队列共纳入 28 例患者，CSF 和血浆分别可用于 26 例患者。CSF 细胞游离 DNA (cfDNA)、CSF 沉淀物和血浆样本中分别有 100% (26/26)、84.6% (22/26)和 73.1% (19/26)检测到驱动基因；92.3% (24/26)的患者 CSF cfDNA 的等位基因分数明显高于其他两种介质。CSF cfDNA 与血浆和原发组织的基因图谱存在差异。CSF cfDNA 中主要发现了多个拷贝数变异 (CNV)，47.8% (11/23)的患者存在 MET 拷贝数增加，其他 CNV 包括 ERBB2、KRAS、ALK 和 MYC。此外，73.1% (19/26)的 CSF cfDNA 中存在 TP53 杂合性丢失 (LOH)，高于血浆中的 2/26 (7.7%；P < 0.001)。TP53 LOH 患者中同时存在耐药突变的频率高于无 LOH 患者(70.6% 比 33.3%；P = 0.162)。在经历 TKI 进展的患者中，CSF cfDNA 中有 30.4% (7/23)的患者检测到 EGFR T790M。
结论
CSF cfDNA 可揭示 LM 的独特基因图谱，应被视为 EGFR 突变型 NSCLC 患者 LM 最具代表性的液体活检介质。
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