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.

中文翻译：

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脑脊液无细胞DNA在EGFR突变型非小细胞肺癌的脑膜脑转移中的独特遗传特征：液体活检的新媒介。

背景在具有表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）中，软脑膜转移瘤（LM）更为常见。由于进入软脑膜病变的途径有限，本研究的目的是探讨脑脊液（CSF）作为LM患者液体活检来源的潜在作用。患者和方法通过下一代测序测试了患有LM的NSCLC中的原发性肿瘤，CSF和血浆。总共入选了45名疑似LM的腰椎穿刺患者，并纳入了那些被诊断为LM的EGFR突变的患者。结果该队列共纳入28例患者。脑脊液和血浆分别可用于26例患者。在100％（26/26），84.6％（22/26）和73.1％（19/26）的样本中检测到驱动基因，这些样本包含CSF无细胞DNA（cfDNA），CSF沉淀物，和等离子；92.3％（24/26）的患者的CSF cfDNA等位基因分数比其他两种培养基高得多。与血浆和原发组织相比，CSF cfDNA捕获了独特的遗传图谱。多拷贝数变异（CNV）主要在CSF cfDNA中鉴定，最常见的是在47.8％（11/23）的患者中发现MET拷贝数增加，而其他CNV包括ERBB2，KRAS，ALK和MYC。此外，在73.1％（19/26）的CSF cfDNA中发现了TP53的杂合性（LOH）丢失，这远高于血浆中的（2/26，7.7％; P <0.001）。TP53 LOH患者的耐药性突变频率比无突变者高（70.6％对33.3％； P = 0.162）。在30例CSF cfDNA中鉴定出EGFR T790M。4％（7/23）的患者经历了TKI进展。结论CSF cfDNA可以揭示LM的独特遗传特征，应被认为是EGFR突变型NSCLC中LM最有代表性的液体活检介质。