禹金良, 盛致远, 高玉帅, 闫兆月, 孙勇, 步星耀. CSF-ctDNA与TIF-ctDNA检测在脑胶质瘤中的临床应用研究[J]. 中国肿瘤临床, 2020, 47(16): 817-822. DOI: 10.3969/j.issn.1000-8179.2020.16.654
引用本文: 禹金良, 盛致远, 高玉帅, 闫兆月, 孙勇, 步星耀. CSF-ctDNA与TIF-ctDNA检测在脑胶质瘤中的临床应用研究[J]. 中国肿瘤临床, 2020, 47(16): 817-822. DOI: 10.3969/j.issn.1000-8179.2020.16.654
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Yu Jinliang, Sheng Zhiyuan, Gao Yushuai, Yan Zhaoyue, Sun Yong, Bu Xingyao. Clinical application of CSF-ctDNA and TIF-ctDNA detection in brain glioma[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2020, 47(16): 817-822. DOI: 10.3969/j.issn.1000-8179.2020.16.654
Citation: Yu Jinliang, Sheng Zhiyuan, Gao Yushuai, Yan Zhaoyue, Sun Yong, Bu Xingyao. Clinical application of CSF-ctDNA and TIF-ctDNA detection in brain glioma[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2020, 47(16): 817-822. DOI: 10.3969/j.issn.1000-8179.2020.16.654
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CSF-ctDNA与TIF-ctDNA检测在脑胶质瘤中的临床应用研究

Clinical application of CSF-ctDNA and TIF-ctDNA detection in brain glioma

    摘要
  • 摘要:
      目的  探讨脑脊液（cerebrospinal fluid，CSF）来源的循环肿瘤DNA（circulating tumor DNA，ctDNA）与肿瘤间质液（tumor interstitial fluid，TIF）ctDNA检测在脑胶质瘤中的诊断、复发监测、肿瘤标志物及靶向药物筛选方面的应用价值。
      方法  收集2019年1月至12月河南省人民医院12例脑胶质瘤患者CSF标本、TIF标本及血液标本。CSF标本、TIF标本进行二代基因测序（next generation sequencing，NGS）检测ctDNA突变，血液标本进行白细胞胚系突变检测，二者对比筛选出肿瘤突变基因。与临床资料结合，对胶质瘤患者CSF-ctDNA与TIF-ctDNA检测结果进行对比及生物信息学分析。
      结果  检测到57种基因变异类型共209个，标本总平均突变数为8.7个，CSF-ctDNA平均突变数为4.3个，TIF-ctDNA平均突变数为13个。9例CSF-ctDNA检测阳性率为（75.0%）、11例TIF-ctDNA检测阳性率（91.6%）。同1例患者ctDNA浓度TIF标本高于CSF标本，TIF标本ctDNA平均浓度（3.38 ng/μL）高于CSF标本中ctDNA平均浓度（0.58 ng/μL）。ctDNA检测发现肿瘤基因突变，较影像学发现复发时间平均提前2.9个月。突变基因PIK3CA、PTEN、KRAS、EGFR、TP53、NF1、BRCA1、BRCA2、TSC1、TSC2、IDH1、CDKN2A匹配到靶向潜在获益药物，突变基因PIK3CA、KRAS、EGFR匹配到潜在耐药药物。
      结论  CSF-ctDNA与TIF-ctDNA能够比影像学更早发现肿瘤复发，是一种可行的能够在肿瘤的发生和复发的过程反复检测、筛选胶质瘤标志物的方法，对胶质瘤患者基因诊断及靶向治疗有一定临床指导作用。相对于CSF-ctDNA，TIF-ctDNA检测获得样本ctDNA浓度更高，检测患者基因平均突变数更多、检测阳性率与检测效力更高，能够提供更多、全面的肿瘤基因组信息，适合临床用于获取胶质瘤的基因表达信息。

     

    Abstract:
      Objective  This clinical study examined circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) and tumor interstitial fluid (TIF) in the diagnosis and monitoring of glioma, and the value of these ctDNAs in targeted drug screening.
      Methods  CSF, TIF, and blood specimens were collected from patients diagnosed with brain glioma. Next generation sequencing was performed in CSF and TIF to detect ctDNA mutations. Leucocyte germ line mutations were detected in blood specimens. Tumor mutation genes were screened out by comparing the testing result. Combined with clinical data, the results of CSF-ctDNA and TIF-ctDNA detection in glioma patients were compared and bioinformatics analysis was performed.
      Results  A total of 209 variants of 57 gene types were detected. The average number of mutations in the samples was 8.7. with an average of 4.3 in CSF-ctDNA and 13 in TIF-ctDNA. The positive rate of CSFctDNA and TIF-ctDNA detection was 75.0% (n=9) and 91.6% (n=11), respectively. The TIF-ctDNA concentration of the same patient was higher than that of CSF-ctDNA. The average TIF-ctDNA concentration was higher than that of CSF-ctDNA (3.38 ng/μL vs. 0.58 ng/μL). The time of recurrence was 2.9 months earlier by ctDNA testing than that of imaging diagnosis. Twelve mutated genes (PIK3CA, PTEN, KRAS, EGFR, TP53, NF1, BRCA1, BRCA2, TSC1, TSC2, IDH1, and CDKN2A) were matched to potentially beneficial drugs. The PIK3CA, KRAS, and EGFR mutated genes were matched to drugs with the potential for development of resistance.
      Conclusions  Examination of CSF-ctDNA and TIF-ctDNA can detect tumor recurrence earlier than imaging. The approach is feasible for the repeated detection and screening of glioma markers in tumor occurrence and recurrence, and can inform gene diagnosis and targeted therapy of glioma patients. The concentration of TIF-ctDNA in samples was greater than that of CSF-ctDNA. The average number, positive rate, and detection efficiency of gene mutations in glioma patients were higher in TIF-ctDNA testing. These higher values can provide more comprehensive tumor genome data and are more suitable to obtain gene expression information about glioma patients in clinical practice.

     

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