Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
Nature. 2018 Nov;563(7732):579-583. doi: 10.1038/s41586-018-0703-0. Epub 2018 Nov 14.
The use of liquid biopsies for cancer detection and management is rapidly gaining prominence. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.
液体活检在癌症检测和管理中的应用正迅速受到关注。目前，使用游离 DNA 检测循环肿瘤 DNA 的方法涉及对体细胞突变进行测序，但鉴于早期癌症患者的复发突变数量有限，这些方法的灵敏度可能较低。相比之下，大规模的表观遗传改变——具有组织和癌症类型特异性——不会受到类似的限制，因此有可能在早期疾病患者中更有能力检测和分类癌症。在这里，我们开发了一种灵敏的、基于免疫沉淀的方法来分析少量循环游离 DNA 的甲基组，并证明了检测富含肿瘤特异性模式的大规模 DNA 甲基化变化的能力。我们还在来自几种肿瘤类型的大量血浆样本中展示了稳健的癌症检测和分类性能。这项工作为基于血浆游离 DNA 甲基化模式进行早期癌症的微创检测、拦截和分类建立生物标志物奠定了基础。
