Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer
Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer
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DOI：
10.1002/cam4.1913
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发表时间：
2019-01-01
期刊：
影响因子：
4
通讯作者：
Zembutsu, Hitoshi
中科院分区：
文献类型：
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作者：
Osumi, Hiroki;Shinozaki, Eiji;Zembutsu, Hitoshi
由于只关注一个或几个基因的循环肿瘤DNA(CtDNA)研究不太可能发现其临床意义，因此建立覆盖数百个突变热点的无细胞DNA(CfDNA)小组对于建立临床实用的ctDNA检测系统具有重要意义。我们招募了101名接受化疗的转移性结直肠癌(MCRC)患者。应用下一代测序技术(NGS)对14个结直肠癌常见突变基因进行了血浆中基于扩增的基因组图谱分析，以评估该方法的可行性，并与其临床参数和匹配组织样本中RAS状态进行比较。88例(87.1%)mCRC患者检测到血浆cfDNA中14个基因的体细胞突变。TP53、KRAS和APC基因突变分别为70例(69.3%)、39例(38.6%)和24例(23.7%)。血浆突变等位基因频率与肿瘤转移(肝脏，P=0.00004，淋巴结，P=0.008，转移器官数，P=0.0006)，肿瘤标志物(癌胚抗原，P=0.000007，CA19-9，P=0.006，乳酸脱氢酶，P=0.00001)，肿瘤直径(最大，P=0.00002，直径总和，P=0.00009)显著相关。CtDNA与配对组织RAS状态的总符合率为77.2%(78/101)。我们的数据证实，基于扩增的NGS系统可以灵敏地检测到cfDNA中的突变等位基因。这些结果表明，ctDNA可能成为监测mCRC患者突变状态和肿瘤负担变化的一种新的诊断生物标志物。
Because circulating tumor DNA (ctDNA) studies focusing on only one or a few genes to monitor the disease progress or treatment response are unlikely to find its clinical significance, the development of cell-free DNA (cfDNA) panel covering hundreds of mutation hot spots is important for the establishment of clinically practical ctDNA detection system. We enrolled 101 patients with metastatic colorectal cancer (mCRC) who received chemotherapy. Amplicon-based genomic profiling of 14 genes, which are commonly mutated in CRC, in plasma by next-generation sequencing (NGS) was carried out to evaluate the feasibility of this assay and was compared with their clinical parameters and RAS status in matched tissue samples. Somatic mutations of the 14 genes in plasma cfDNA were detected in 88 patients (87.1%) with mCRC. Mutations in TP53, KRAS, and APC genes were detected in 70 (69.3%), 39 (38.6%), and 24 (23.7%) patients, respectively. Mutant allele frequencies in plasma were significantly associated with metastasis (liver, P = 0.00004, lymph node, P = 0.008, number of metastatic organs, P = 0.0006), tumor markers (CEA, P = 0.000007, CA19-9, P = 0.006, LDH, P = 0.00001), and tumor diameter (maximum, P = 0.00002, sum of diameter, P = 0.00009). The overall concordance rate of RAS status between ctDNA and matched tissue was 77.2% (78/101). Our data confirmed that mutant allele in cfDNA can be sensitively detected by amplicon-based NGS system. These results suggest that ctDNA could be a novel diagnostic biomarker to monitor changes in mutational status and tumor burden in patients with mCRC.