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

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

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32995-6

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