Volume 27, No 10, Oct 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 10, October 2017: 1231-1242   |  Open Access

ORIGINAL ARTICLES

5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages

Chun-Xiao Song^1,13,*, Senlin Yin^2,3,*, Li Ma^4,5, Amanda Wheeler⁵, Yu Chen², Yan Zhang⁶, Bin Liu^6,7, Junjie Xiong⁸, Weihan Zhang⁹, Jiankun Hu⁹, Zongguang Zhou⁹, Biao Dong², Zhiqi Tian¹⁰, Stefanie S Jeffrey⁵, Mei-Sze Chua^4,5, Samuel So^4,5, Weimin Li¹¹, Yuquan Wei², Jiajie Diao¹⁰, Dan Xie^2,9,11 and Stephen R Quake^1,12

¹Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA
²State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, Sichuan 610041, China
³Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
⁴Asian Liver Center, Stanford University School of Medicine, Stanford, CA 94305, USA
⁵Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
⁶Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
⁷Department of Pulmonary Tumor Ward, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, China
⁸Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
⁹Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
¹⁰Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
¹¹Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
¹²Chan Zuckerberg Biohub, San Francisco, CA 94518, USA
¹³Current address: Ludwig Institute for Cancer Research and Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK Correspondence: Stephen R Quake, Tel: +1 650 736 7890 E-mail: quake@stanford.edu; Dan Xie,(danxie@scu.edu.cn)

5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.

10.1038/cr.2017.106

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