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首页> 美国卫生研究院文献>Molecular Oncology >Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA primary tumor and metastases from patients undergoing resection of colorectal liver metastases
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Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA primary tumor and metastases from patients undergoing resection of colorectal liver metastases

机译：使用各种靶向检测方法对结直肠癌肝转移患者的循环肿瘤DNA原发肿瘤和转移瘤配对样本进行体细胞突变检测

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Assessing circulating tumor DNA (ctDNA) is a promising method to evaluate somatic mutations from solid tumors in a minimally‐invasive way. In a group of twelve metastatic colorectal cancer (mCRC) patients undergoing liver metastasectomy, from each patient DNA from cell‐free DNA (cfDNA), the primary tumor, metastatic liver tissue, normal tumor‐adjacent colon or liver tissue, and whole blood were obtained. Investigated was the feasibility of a targeted NGS approach to identify somatic mutations in ctDNA. This targeted NGS approach was also compared with NGS preceded by mutant allele enrichment using synchronous coefficient of drag alteration technology embodied in the OnTarget assay, and for selected mutations with digital PCR (dPCR). All tissue and cfDNA samples underwent IonPGM sequencing for a CRC‐specific 21‐gene panel, which was analyzed using a standard and a modified calling pipeline. In addition, cfDNA, whole blood and normal tissue DNA were analyzed with the OnTarget assay and with dPCR for specific mutations in cfDNA as detected in the corresponding primary and/or metastatic tumor tissue. NGS with modified calling was superior to standard calling and detected ctDNA in the cfDNA of 10 patients harboring mutations in APC, ATM, CREBBP, FBXW7, KRAS, KMT2D, PIK3CA and TP53. Using this approach, variant allele frequencies in plasma ranged predominantly from 1 to 10%, resulting in limited concordance between ctDNA and the primary tumor (39%) and the metastases (55%). Concordance between ctDNA and tissue markedly improved when ctDNA was evaluated for KRAS, PIK3CA and TP53 mutations by the OnTarget assay (80%) and digital PCR (93%). Additionally, using these techniques mutations were observed in tumor‐adjacent tissue with normal morphology in the majority of patients, which were not observed in whole blood. In conclusion, in these mCRC patients with oligometastatic disease NGS on cfDNA was feasible, but had limited sensitivity to detect all somatic mutations present in tissue. Digital PCR and mutant allele enrichment before NGS appeared to be more sensitive to detect somatic mutations.
机译：评估循环肿瘤DNA（ctDNA）是一种以微创方式评估实体瘤的体细胞突变的有前途的方法。在一组12例行肝转移切除术的转移性结直肠癌（mCRC）患者中，每位患者的无细胞DNA（cfDNA）DNA，原发性肿瘤，转移性肝组织，正常肿瘤邻近结肠或肝组织以及全血都是获得。研究了靶向NGS方法鉴定ctDNA中体细胞突变的可行性。还将这种靶向的NGS方法与NGS进行了比较，之后使用OnTarget分析中包含的同步拖曳改变系数技术，通过突变等位基因富集进行了等位基因富集，并使用数字PCR（dPCR）对选定的突变进行了比较。所有组织和cfDNA样本均经过IonPGM测序，用于CRC特异性21基因检测组，并使用标准和改进的调用管道进行了分析。另外，用OnTarget测定法和dPCR对cfDNA，全血和正常组织DNA进行了分析，以确定在相应的原发性和/或转移性肿瘤组织中检测到的cfDNA中的特定突变。带有改良呼叫的NGS优于标准呼叫，在10例APC，ATM，CREBBP，FBXW7，KRAS，KMT2D，PIK3CA和TP53突变的患者的cfDNA中检测到ctDNA。使用这种方法，血浆中的变异等位基因频率主要在1％到10％之间变化，从而导致ctDNA与原发肿瘤（39％）和转移瘤（55％）之间的一致性有限。当通过OnTarget分析（80％）和数字PCR（93％）评估ctDNA的KRAS，PIK3CA和TP53突变时，ctDNA与组织之间的一致性显着提高。此外，使用这些技术，在大多数患者中，在形态正常的肿瘤邻近组织中观察到突变，而在全血中未观察到。总之，在这些具有cfDNA少转移性疾病的mCRC患者中，可行，但检测组织中存在的所有体细胞突变的敏感性有限。 NGS之前的数字PCR和突变等位基因富集似乎对检测体细胞突变更为敏感。

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