Journal Article

Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer

Stackpole, Mary L., Tomlinson, James S., He, Shanshan, Yuan, Zuyang, Wong, Wing Hung, Han, Steven-Huy B., Lee, Yi-Te, Saab, Sammy, Tran, Benjamin, Li, Wenyuan, Li, Qingjiao, Choi, Gina, Dry, Sarah, Aberle, Denise R., French, Samuel, Tseng, Hsian-Rong, Noor, Zorawar, Li, Paul Shize, Zeng, Weihua, Geschwind, Daniel, Li, Shuo, Magyar, Clara E., Yildirim, Asli, Alber, Frank, Sun, Fengzhu, Lajonchere, Clara, Zhou, Xianghong Jasmine, Zhou, Yonggang, Ahuja, Preeti, Chen, Pin-Jung, Dubinett, Steven M., Liu, Chun-Chi, Garon, Edward, Agopian, Vatche, Zhu, Yazhen, Yokomizo, Megumi, Wang, Ziye, Ni, Xiaohui, Yeh, Angela, Winograd, Paul

2022

Overview

Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow. Early cancer detection by cell-free DNA (cfDNA) is challenged by the low amount of tumour DNA in cfDNA, tumour heterogeneity and the small patient cohorts. Here, the authors develop a method, cfMethyl-Seq, for cost-effective methylome profiling of cfDNA and for detecting and locating cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 631/114 / 631/114/2415 / 631/114/794 / 631/67/2322 / 692/308/53/2421 / Abnormalities / Bisulfite / Cancer / Cell-Free Nucleic Acids - genetics / Colon / Computer applications / Cost-Benefit Analysis / CpG islands / Deoxyribonucleic acid / DNA / DNA methylation / DNA sequencing / Early Detection of Cancer / Epigenome / Gastric cancer / Genomes / Heterogeneity / Humanities and Social Sciences / Humans / Information processing / Liver cancer / Lung cancer / multidisciplinary / Science / Science (multidisciplinary) / Stomach Neoplasms - diagnosis / Stomach Neoplasms - genetics / Tumors