The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients
The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients
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DOI：
10.1158/1078-0432.ccr-17-3837
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发表时间：
2018-08-01
影响因子：
11.5
通讯作者：
Talasaz, AmirAli
中科院分区：
文献类型：
--
作者：
Zill, Oliver A.;Banks, Kimberly C.;Talasaz, AmirAli
目的：无细胞DNA(CfDNA)测序为获得可操作的基因组信息以指导个体化癌症治疗提供了一种非侵入性方法，但与治疗相关的循环中的多种变化和肿瘤异质性的存在使所观察到的变异的解释复杂化。实验设计：我们描述了cfDNA深度测序分析的21,807例晚期癌症患者的70个癌症基因的体细胞突变图景。为了便于解释晚期癌症患者循环中肿瘤DNA的基因组复杂性，我们开发了识别cfDNA拷贝数驱动因素改变和cfDNA克隆性的方法。结果：非小细胞肺癌、乳腺癌和结直肠癌主要驱动基因的cfDNA改变模式和发生率与肿瘤组织测序汇编(癌症基因组图谱和COSMIC；r=0.90-0.99)中的模式和发生率基本一致，改变发生率的主要差异是由于患者的治疗。这种高度敏感的cfDNA测序分析揭示了许多亚克隆性肿瘤起源的改变，预计是克隆进化的结果，但导致明显背离了治疗初期肿瘤的相互排他性。在应用新的cfDNA克隆性和拷贝数驱动程序识别方法后，在预测的主干驱动程序cfDNA改变(EGFR和ERBB2的FDR=5 x 10(-7))之间观察到了稳健的互斥性，有效地区分了肿瘤起始改变和继发性改变。与治疗相关的耐药性，包括新的改变和平行进化，在cfDNA队列中很常见，并在有靶向性驱动因素改变的患者中丰富(>；18.6%的患者)。结论：这些对大量cfDNA测序数据集的回顾分析揭示了晚期实体肿瘤的亚克隆结构和新出现的耐药性。(C)2018年AACR。
Purpose: Cell-free DNA (cfDNA) sequencing provides a noninvasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (The Cancer Genome Atlas and COSMIC; r = 0.90-0.99), with the principal differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naive tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR = 5 x 10(-7) for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel alterations and parallel evolution, was common in the cfDNA cohort and was enriched in patients with targetable driver alterations (>18.6% patients).Conclusions: Together, these retrospective analyses of a large cfDNA sequencing data set reveal subclonal structures and emerging resistance in advanced solid tumors. (C) 2018 AACR.