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

• Published in: Nature communications Vol. 13; no. 1; p. 5566
• Main Authors: Stackpole, Mary L., Zeng, Weihua, Li, Shuo, Liu, Chun-Chi, Zhou, Yonggang, He, Shanshan, Yeh, Angela, Wang, Ziye, Sun, Fengzhu, Li, Qingjiao, Yuan, Zuyang, Yildirim, Asli, Chen, Pin-Jung, Winograd, Paul, Tran, Benjamin, Lee, Yi-Te, Li, Paul Shize, Noor, Zorawar, Yokomizo, Megumi, Ahuja, Preeti, Zhu, Yazhen, Tseng, Hsian-Rong, Tomlinson, James S., Garon, Edward, French, Samuel, Magyar, Clara E., Dry, Sarah, Lajonchere, Clara, Geschwind, Daniel, Choi, Gina, Saab, Sammy, Alber, Frank, Wong, Wing Hung, Dubinett, Steven M., Aberle, Denise R., Agopian, Vatche, Han, Steven-Huy B., Ni, Xiaohui, Li, Wenyuan, Zhou, Xianghong Jasmine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32995-6

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.