Background Hepatocellular carcinomas (HCCs) are not routinely biopsied, resulting in a lack of tumor materials for molecular profiling. Here we sought to determine whether plasma-derived cell-free DNA (cfDNA) captures the genetic alterations of HCC in patients who have not undergone systemic therapy. Patients and methods Frozen biopsies from the primary tumor and plasma were synchronously collected from 30 prospectively recruited, systemic treatment-naïve HCC patients. Deep sequencing of the DNA from the biopsies, plasma-derived cfDNA and matched germline was carried out using a panel targeting 46 coding and non-coding genes frequently altered in HCCs. Results In 26/30 patients, at least one somatic mutation was detected in biopsy and/or cfDNA. Somatic mutations in HCC-associated genes were present in the cfDNA of 63% (19/30) of the patients and could be detected 'de novo' without prior knowledge of the mutations present in the biopsy in 27% (8/30) of the patients. Mutational load and the variant allele fraction of the mutations detected in the cfDNA positively correlated with tumor size and Edmondson grade. Crucially, among the seven patients in whom the largest tumor was ≥5 cm or was associated with metastasis, at least one mutation was detected 'de novo' in the cfDNA of 86% (6/7) of the cases. In these patients, cfDNA and tumor DNA captured 87% (80/92) and 95% (87/92) of the mutations, suggesting that cfDNA and tumor DNA captured similar proportions of somatic mutations. Conclusion In patients with high disease burden, the use of cfDNA for genetic profiling when biopsy is unavailable may be feasible. Our results support further investigations into the clinical utility of cfDNA in a larger cohort of patients.

中文翻译：

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未治疗的肝细胞癌患者中使用血浆来源的无细胞DNA进行基因分析：一项前瞻性研究。

背景技术肝细胞癌（HCC）不能常规活检，导致缺乏用于分子谱分析的肿瘤材料。在这里，我们试图确定血浆来源的无细胞DNA（cfDNA）是否捕获了未接受全身治疗的患者中HCC的遗传改变。患者和方法从30名前瞻性，未接受过全身治疗的HCC患者中同步收集原发性肿瘤和血浆的冷冻活检。使用针对46种在HCC中经常发生变化的编码和非编码基因的研究小组，对活检组织，血浆来源的cfDNA和匹配的种系的DNA进行了深度测序。结果在26/30患者中，活检和/或cfDNA中至少检测到一种体细胞突变。HCC相关基因的体细胞突变存在于63％（19/30）的患者的cfDNA中，并且无需事先了解活检中27％（8/30）存在的突变即可“从头”检测到。病人。在cfDNA中检测到的突变的突变量和变异等位基因分数与肿瘤大小和埃德蒙森等级呈正相关。至关重要的是，在最大肿瘤≥5cm或与转移相关的七名患者中，有86％（6/7）的患者的cfDNA中至少检测到一种“从头突变”。在这些患者中，cfDNA和肿瘤DNA捕获了87％（80/92）和95％（87/92）的突变，这表明cfDNA和肿瘤DNA捕获了相似比例的体细胞突变。结论在疾病负担高的患者中，当无法进行活检时，使用cfDNA进行基因分析可能是可行的。我们的结果支持对更多患者中cfDNA的临床应用进行进一步研究。