Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
IMED Asia, AstraZeneca, Shanghai, China.
Clin Cancer Res. 2018 Jan 1;24(1):209-216. doi: 10.1158/1078-0432.CCR-17-1582. Epub 2017 Oct 13.
Leptomeningeal metastasis (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor () mutation-positive NSCLC patients with LM. The status of -activating mutations was highly concordant between primary tumor and CSF. aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development. Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. .
脑膜转移（LM）是非小细胞肺癌（NSCLC）的一种有害并发症，与预后不良有关。然而，转移过程的潜在机制仍知之甚少。我们对表皮生长因子受体（）突变阳性 NSCLC 伴 LM 患者的原发肿瘤组织、脑脊液（CSF）和配对正常对照进行了下一代面板测序。原发肿瘤和 CSF 之间的 -激活突变状态高度一致。这些患者的 异常率很高，提示与 LM 风险相关。有趣的是，配对 CSF 和原发性病变之间观察到体细胞蛋白改变变异的低重叠，表现出肿瘤异质性和遗传分歧。此外，CSF 中反复出现的基因组改变的基因主要涉及细胞周期调控和 DNA 损伤反应（DDR），提示该途径在 LM 发展中的作用。我们的研究阐明了 NSCLC-LM 的基因组变化，显示了遗传异质性和分歧，揭示了细胞周期和 DDR 途径的参与，并为这一未满足的医疗需求的潜在治疗方法铺平了道路。
