Institute of Pathology, University Hospital Basel, Basel; Hepatology Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
Department of Transplantation - Liver Unit, Cardarelli Hospital, Naples.
Ann Oncol. 2018 May 1;29(5):1286-1291. doi: 10.1093/annonc/mdy083.
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.
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.
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.
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.
肝细胞癌（HCC）通常不进行活检，导致缺乏肿瘤的分子谱分析材料。在这里，我们试图确定未接受系统治疗的患者的血浆游离 DNA（cfDNA）是否能捕获 HCC 的遗传改变。
从 30 名前瞻性招募的、未经系统治疗的 HCC 患者中同步采集原发肿瘤的冷冻活检和血浆。使用针对 HCC 中经常发生改变的 46 个编码和非编码基因的panel，对活检、血浆衍生的 cfDNA 和匹配的种系 DNA 进行深度测序。
在 30 例患者中，至少在 26/30 例患者的活检和/或 cfDNA 中检测到一个体细胞突变。在 63%（19/30）的患者的 cfDNA 中存在与 HCC 相关基因的体细胞突变，并且在 27%（8/30）的患者中可以在没有预先知道活检中存在的突变的情况下“从头”检测到。cfDNA 中检测到的突变的突变负荷和变异等位基因分数与肿瘤大小和 Edmondson 分级呈正相关。至关重要的是，在 7 名最大肿瘤直径≥5cm 或存在转移的患者中，至少有一个突变在 cfDNA 中“从头”检测到，占 86%（6/7）。在这些患者中，cfDNA 和肿瘤 DNA 分别捕获了 87%（80/92）和 95%（87/92）的突变，表明 cfDNA 和肿瘤 DNA 捕获了相似比例的体细胞突变。
在疾病负担较高的患者中，当活检不可用时，使用 cfDNA 进行基因谱分析可能是可行的。我们的结果支持在更大的患者队列中进一步研究 cfDNA 的临床应用。
