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; Xianghong Jasmine Zhou

doi:10.1038/s41467-022-32995-6

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

Nat Commun. 2022 Sep 29;13(1):5566. doi: 10.1038/s41467-022-32995-6.

Authors

Mary L Stackpole^#^{1

2}, Weihua Zeng^#¹, Shuo Li^#^{1

2}, Chun-Chi Liu², Yonggang Zhou¹, Shanshan He¹, Angela Yeh¹, Ziye Wang¹, Fengzhu Sun³, Qingjiao Li⁴, Zuyang Yuan¹, Asli Yildirim⁵, Pin-Jung Chen⁶, Paul Winograd⁶, Benjamin Tran⁶, Yi-Te Lee⁷, Paul Shize Li⁸, Zorawar Noor⁹, Megumi Yokomizo¹⁰, Preeti Ahuja^{10

11}, Yazhen Zhu^{7

11}, Hsian-Rong Tseng^{7

11}, James S Tomlinson^{6

9

11

12}, Edward Garon^{9

11}, Samuel French^{1

11}, Clara E Magyar^{1

11}, Sarah Dry^{1

11}, Clara Lajonchere^{11

13}, Daniel Geschwind¹³, Gina Choi⁹, Sammy Saab⁹, Frank Alber^{5

14}, Wing Hung Wong^{15

16}, Steven M Dubinett^{1

7

9

11

12}, Denise R Aberle^{10

11}, Vatche Agopian^{17

18}, Steven-Huy B Han¹⁹, Xiaohui Ni²⁰, Wenyuan Li²¹, Xianghong Jasmine Zhou^{22

23

24}

Affiliations

¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
² EarlyDiagnostics, Inc., 570 Westwood Plaza, Los Angeles, CA, 90095, USA.
³ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA.
⁴ The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
⁵ Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
⁶ Department of Surgery, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
⁷ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
⁸ Westlake High School, 100N Lakeview Cyn Road, Westlake Village, CA, 91362, USA.
⁹ Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
¹⁰ Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
¹¹ Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
¹² VA Greater Los Angeles Health Care System, Los Angeles, CA, 90073, USA.
¹³ Institute for Precision Health, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
¹⁴ Institute for Quantitative and Computational Biosciences, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
¹⁵ Department of Statistics, Stanford University, Stanford, CA, 94305, USA.
¹⁶ Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA.
¹⁷ Department of Surgery, University of California at Los Angeles, Los Angeles, CA, 90095, USA. vagopian@mednet.ucla.edu.
¹⁸ Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA. vagopian@mednet.ucla.edu.
¹⁹ Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA. steven.han@ucla.edu.
²⁰ EarlyDiagnostics, Inc., 570 Westwood Plaza, Los Angeles, CA, 90095, USA. xiaohui.ni@earlydx.com.
²¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA. wenyuanli@mednet.ucla.edu.
²² Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA. xjzhou@mednet.ucla.edu.
²³ Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA. xjzhou@mednet.ucla.edu.
²⁴ Institute for Quantitative and Computational Biosciences, University of California at Los Angeles, Los Angeles, CA, 90095, USA. xjzhou@mednet.ucla.edu.

^# Contributed equally.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell-Free Nucleic Acids* / genetics
Cost-Benefit Analysis
Early Detection of Cancer
Epigenome
Humans
Stomach Neoplasms* / diagnosis
Stomach Neoplasms* / genetics

Substances

Cell-Free Nucleic Acids

Abstract

Publication types

MeSH terms

Substances

Grants and funding