Introduction SCLC accounts for approximately 250,000 deaths worldwide each year. Acquisition of adequate tumor biopsy samples is challenging, and liquid biopsies present an alternative option for patient stratification and response monitoring. Methods We applied whole genome next-generation sequencing to circulating free DNA (cfDNA) from 39 patients with limited-stage (LS) SCLC and 30 patients with extensive-stage SCLC to establish genome-wide copy number aberrations and also performed targeted mutation analysis of 110 SCLC associated genes. Quantitative metrics were calculated for copy number aberrations, including percent genome amplified (PGA [the percentage of genomic regions amplified]), Z-score (a measure of standard deviation), and Moran’s I (a measure of spatial autocorrelation). In addition CellSearch, an epitope-dependent enrichment platform, was used to enumerate circulating tumor cells (CTCs) from a parallel blood sample. Results Genome-wide and targeted cfDNA sequencing data identified tumor-related changes in 94% of patients with LS SCLC and 100% of patients with extensive-stage SCLC. Parallel analysis of CTCs based on at least 1 CTC/7.5 mL of blood increased tumor detection frequencies to 95% for LS SCLC. Both CTC counts and cfDNA readouts correlated with disease stage and overall survival. Conclusions We demonstrate that a simple cfDNA genome-wide copy number approach provides an effective means of monitoring patients through treatment and show that targeted cfDNA sequencing identifies potential therapeutic targets in more than 50% of patients. We are now incorporating this approach into additional studies and trials of targeted therapies.

中文翻译：

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使用靶向全基因组测序对小细胞肺癌患者的循环游离 DNA 进行分析


简介 SCLC 每年导致全球约 25 万人死亡。获取足够的肿瘤活检样本具有挑战性，液体活检为患者分层和反应监测提供了另一种选择。方法 我们对 39 名局限性 (LS) SCLC 患者和 30 名广泛期 SCLC 患者的循环游离 DNA (cfDNA) 应用全基因组新一代测序，以确定全基因组拷贝数畸变，并对110 个 SCLC 相关基因。计算拷贝数畸变的定量指标，包括基因组扩增百分比（PGA [扩增的基因组区域的百分比]）、Z 分数（标准偏差的度量）和 Moran's I（空间自相关的度量）。此外，CellSearch（一种表位依赖性富集平台）用于从平行血液样本中计数循环肿瘤细胞（CTC）。结果全基因组和靶向 cfDNA 测序数据确定了 94% 的 LS SCLC 患者和 100% 的广泛期 SCLC 患者的肿瘤相关变化。基于至少 1 个 CTC/7.5 mL 血液的 CTC 并行分析将 LS SCLC 的肿瘤检出率提高到 95%。 CTC 计数和 cfDNA 读数均与疾病阶段和总体生存率相关。结论 我们证明，简单的 cfDNA 全基因组拷贝数方法提供了一种通过治疗监测患者的有效方法，并表明靶向 cfDNA 测序可以识别超过 50% 的患者的潜在治疗靶点。我们现在正在将这种方法纳入靶向治疗的其他研究和试验中。