Cell-free DNA TAPS provides multimodal information for early cancer detection

Paulina Siejka-Zielińska; Jingfei Cheng; Felix Jackson; Yibin Liu; Zahir Soonawalla; Srikanth Reddy; Michael Silva; Luminita Puta; Misti Vanette McCain; Emma L Culver; Noor Bekkali; Benjamin Schuster-Böckler; Pier Francesco Palamara; Derek Mann; Helen Reeves; Eleanor Barnes; Shivan Sivakumar; Chun-Xiao Song

doi:10.1126/sciadv.abh0534

Cell-free DNA TAPS provides multimodal information for early cancer detection

Sci Adv. 2021 Sep 3;7(36):eabh0534. doi: 10.1126/sciadv.abh0534. Epub 2021 Sep 1.

Authors

Paulina Siejka-Zielińska^{1

2}, Jingfei Cheng^{1

2}, Felix Jackson^{1

2

3}, Yibin Liu^{1

2}, Zahir Soonawalla⁴, Srikanth Reddy⁵, Michael Silva⁶, Luminita Puta¹, Misti Vanette McCain^{7

8}, Emma L Culver⁹, Noor Bekkali¹⁰, Benjamin Schuster-Böckler^{1

11}, Pier Francesco Palamara^{12

13}, Derek Mann^{7

14

15}, Helen Reeves^{7

8

16}, Eleanor Barnes⁹, Shivan Sivakumar^{17

18

19}, Chun-Xiao Song^{1

2}

Affiliations

¹ Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
² Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
³ Department of Computer Science, University of Oxford, Oxford, UK.
⁴ Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁵ Oxford Transplant Centre, Churchill Hospital, Oxford, UK.
⁶ Department of HPB Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁷ Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
⁸ Newcastle University Centre for Cancer, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
⁹ Peter Medawar Building and Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁰ Department of Gastroenterology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
¹¹ Big Data Institute, University of Oxford, Oxford, UK.
¹² Department of Statistics, University of Oxford, Oxford, UK.
¹³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹⁴ Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
¹⁵ Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK.
¹⁶ Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
¹⁷ Department of Oncology, University of Oxford, Oxford, UK.
¹⁸ Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁹ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

Abstract

Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection, but it is technologically challenging. Recently, we developed TET-assisted pyridine borane sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here, we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and noncancer controls. From only 10 ng of cfDNA (1 to 3 ml of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.

Abstract

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