Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Department of Gastroenterological and Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
Mol Oncol. 2020 Aug;14(8):1719-1730. doi: 10.1002/1878-0261.12727. Epub 2020 Jun 8.
As the use of next-generation sequencing (NGS) for plasma cell-free DNA (cfDNA) continues to expand in clinical settings, accurate identification of circulating tumor DNA mutations is important to validate its use in the clinical management for cancer patients. Here, we aimed to characterize mutations including clonal hematopoiesis (CH)-related mutations in plasma cfDNA and tumor tissues using the same ultradeep NGS assay and evaluate the clinical significance of CH-related mutations on the interpretation of liquid biopsy results. Ultradeep targeted NGS using Oncomine Pan-Cancer Panel was performed on matched surgically resected tumor tissues, peripheral blood cells (PBCs), and 120 plasma cfDNA samples from 38 colorectal cancer patients. The clinical significance of the CH-related mutations in plasma cfDNA was evaluated by longitudinal monitoring of the postoperative plasma samples. Among the 38 patients, 74 nonsynonymous mutations were identified from tumor tissues and 64 mutations from the preoperative plasma samples. Eleven (17%) of the 64 mutations identified in plasma cfDNA were also detected in PBC DNA and were identified to be CH-related mutations. Overall, 11 of 38 (29%) patients in this cohort harbored at least one CH-related mutation in plasma cfDNA. These CH-related mutations were continuously detected in subsequent postoperative plasma samples from three patients which could be misinterpreted as the presence of residual disease or as lack of treatment response. Our results indicated that it is essential to integrate the mutational information of PBCs to differentiate tumor-derived from CH-related mutations in liquid biopsy analysis. This would prevent the misinterpretation of results to avoid misinformed clinical management for cancer patients.
随着下一代测序（NGS）在血浆游离 DNA（cfDNA）中的应用在临床环境中不断扩展，准确识别循环肿瘤 DNA 突变对于验证其在癌症患者临床管理中的应用非常重要。在这里，我们旨在使用相同的超深度 NGS 检测方法对血浆 cfDNA 和肿瘤组织中的突变（包括克隆性造血（CH）相关突变）进行特征描述，并评估 CH 相关突变对液体活检结果解释的临床意义。对 38 例结直肠癌患者的 120 份血浆 cfDNA 样本和配对的手术切除肿瘤组织、外周血细胞（PBC）进行了超深度靶向 NGS 检测，采用 Oncomine Pan-Cancer Panel。通过对术后血浆样本的纵向监测来评估血浆 cfDNA 中 CH 相关突变的临床意义。在 38 名患者中，从肿瘤组织中鉴定出 74 个非同义突变，从术前血浆样本中鉴定出 64 个突变。在血浆 cfDNA 中鉴定出的 64 个突变中有 11 个（17%）也存在于 PBC DNA 中，被鉴定为 CH 相关突变。总体而言，该队列中有 11 例（29%）患者的血浆 cfDNA 中至少存在一个 CH 相关突变。这 3 名患者的术后血浆样本中持续检测到这些 CH 相关突变，可能会被错误地解释为残留疾病的存在或缺乏治疗反应。我们的结果表明，在液体活检分析中，必须整合 PBC 的突变信息，以区分肿瘤源性和 CH 相关突变。这将防止结果的错误解释，避免对癌症患者的临床管理产生误解。
