Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore 117583, Singapore.
Institute for Health Innovation and Technology, National University of Singapore, Singapore 117599, Singapore.
Sci Adv. 2022 Sep 9;8(36):eabn4030. doi: 10.1126/sciadv.abn4030.
Genome-wide analysis of cell-free DNA methylation profile is a promising approach for sensitive and specific detection of many cancers. However, scaling such assays for clinical translation is impractical because of the high cost of whole-genome bisulfite sequencing. We show that the small fraction of GC-rich genome is highly enriched in CpG sites and disproportionately harbors most of the cancer-specific methylation signature. Here, we report on the simple and effective heat enrichment of CpG-rich regions for bisulfite sequencing (Heatrich-BS) platform that allows for focused methylation profiling in these highly informative regions. Our novel method and bioinformatics algorithm enable accurate tumor burden estimation and quantitative tracking of colorectal cancer patient's response to treatment at much reduced sequencing cost suitable for frequent monitoring. We also show tumor epigenetic subtyping using Heatrich-BS, which could enable patient stratification. Heatrich-BS holds great potential for highly scalable screening and monitoring of cancer using liquid biopsy.
对游离 DNA 甲基化谱进行全基因组分析是一种很有前途的方法，可用于敏感和特异性检测多种癌症。然而，由于全基因组亚硫酸氢盐测序的成本很高，因此此类检测的临床转化规模是不切实际的。我们发现富含 GC 的基因组的一小部分富含 CpG 位点，并且不成比例地拥有大多数癌症特异性甲基化特征。在这里，我们报告了一种简单有效的富含 CpG 区域的热富集亚硫酸氢盐测序（Heatrich-BS）平台，该平台允许在这些高度信息丰富的区域进行有针对性的甲基化分析。我们的新方法和生物信息学算法能够以降低测序成本的方式，实现对结直肠癌患者肿瘤负担的准确估计和治疗反应的定量跟踪，非常适合频繁监测。我们还展示了使用 Heatrich-BS 进行肿瘤表观遗传亚型分析，这可能使患者分层。Heatrich-BS 具有很大的潜力，可用于通过液体活检进行癌症的高可扩展性筛查和监测。
