Non-small cell lung cancer NSCLC Epigenomics Predictive biomarker Therapy response DNA methylation
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摘要

Abstract Background Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed. Methods Here, we employed patient-derived xenografts (PDXs) to detect predictive methylation biomarkers for platin-based therapies. We used MeDIP-Seq to generate genome-wide DNA methylation profiles of 22 PDXs, their parental primary NSCLC, and their corresponding normal tissues and complemented the data with gene expression analyses of the same tissues. Candidate biomarkers were validated with quantitative methylation-specific PCRs (qMSP) in an independent cohort. Results Comprehensive analyses revealed that differential methylation patterns are highly similar, enriched in PDXs and lung tumor-specific when comparing differences in methylation between PDXs versus primary NSCLC. We identified a set of 40 candidate regions with methylation correlated to carboplatin response and corresponding inverse gene expression pattern even before therapy. This analysis led to the identification of a promoter CpG island methylation of LDL receptor-related protein 12 (LRP12) associated with increased resistance to carboplatin. Validation in an independent patient cohort (n = 35) confirmed that LRP12 methylation status is predictive for therapeutic response of NSCLC patients to platin therapy with a sensitivity of 80% and a specificity of 84% (p 

译文

背景: 非小细胞肺癌 (Non-small cell lung cancer) 是全球范围内癌症相关死亡的最常见原因,主要通过放射治疗、手术、和铂类药物,如顺铂和卡铂。非小细胞肺癌患者治疗的主要挑战是对化疗的固有或获得性耐药性。迫切需要预测患者预后的分子标记。方法在这里,我们采用患者来源的异种移植 (PDXs) 来检测基于铂的治疗的预测性甲基化生物标志物。我们使用 MeDIP-Seq 生成 22 个 PDXs 的全基因组 DNA 甲基化谱,它们的亲代原发性非小细胞肺癌及其相应的正常组织,并用相同组织的基因表达分析补充数据。在独立队列中用定量甲基化特异性 PCRs (qMSP) 验证候选生物标志物。结果综合分析显示,当比较 PDXs 与原发性非小细胞肺癌之间甲基化的差异时,差异甲基化模式高度相似,富含 PDXs 和肺部肿瘤特异性。我们鉴定了一组 40 个与卡铂反应相关的甲基化候选区域,甚至在治疗前就有相应的反向基因表达模式。该分析导致低密度脂蛋白受体相关蛋白 12 (LRP12) 的启动子 CpG 岛甲基化与卡铂耐药性增加相关。在独立患者队列 (n =-35) 中的验证证实 LRP12 甲基化状态可预测非小细胞肺癌患者对铂治疗的治疗反应,敏感性为 80%,特异性为 84% (p

Carboplatin

呼吸 铂类抗肿瘤药 药物
概述  :  

本品为铂类抗肿瘤药,直接作用于DNA,通过破坏DNA而抑制肿瘤的生长。本品在体内与血浆蛋白结合较少,主要经肾脏排泄。本品血浆半衰期较长,为29小时。 适应证 主要用于实体瘤小细胞肺癌,也可用于非小细胞肺癌。 用法用量 本品仅供静脉使用,可单用也可与其他抗癌药联用。肾功能正常的成人初治患者,推荐剂量为400mg/m2,单剂静脉输注60分钟,3-4 周重复

Carboplatin   /,kɑ:bəu'plætin/

释    义   n. 卡铂;顺羧酸铂

例    句   Sequential clinical trials of chemotherapy agents demonstrate that cisplatin (or carboplatin) given in combination with paclitaxel is the most active combination identified. 序贯化疗药物临床试验表明,顺铂(或卡铂)联合紫杉醇是最活跃的组合。

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