Integrated fragmentomic profile and 5-Hydroxymethylcytosine of capture-based low-pass sequencing data enables pan-cancer detection via cfDNA

Zhidong Zhang; Xuenan Pi; Chang Gao; Jun Zhang; Lin Xia; Xiaoqin Yan; Xinlei Hu; Ziyue Yan; Shuxin Zhang; Ailin Wei; Yuer Guo; Jingfeng Liu; Ang Li; Xiaolong Liu; Wei Zhang; Yanhui Liu; Dan Xie

doi:10.1016/j.tranon.2023.101694

Integrated fragmentomic profile and 5-Hydroxymethylcytosine of capture-based low-pass sequencing data enables pan-cancer detection via cfDNA

Transl Oncol. 2023 Aug:34:101694. doi: 10.1016/j.tranon.2023.101694. Epub 2023 May 18.

Authors

Zhidong Zhang¹, Xuenan Pi¹, Chang Gao¹, Jun Zhang², Lin Xia¹, Xiaoqin Yan², Xinlei Hu¹, Ziyue Yan², Shuxin Zhang³, Ailin Wei⁴, Yuer Guo¹, Jingfeng Liu⁵, Ang Li⁶, Xiaolong Liu⁵, Wei Zhang⁷, Yanhui Liu³, Dan Xie⁸

Affiliations

¹ Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, Sichuan Province, P. R. China.
² Tailai Inc., Shanghai 200233, P. R. China.
³ Department of Neurosurgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, Sichuan Province, P. R. China.
⁴ Guang'an People's Hospital, Guang'an, China.
⁵ Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou 350025, Fujian Province, P. R. China.
⁶ Department of Pancreatic Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, Sichuan Province, P. R. China.
⁷ Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of the Second Military Medical University, Shanghai 200433, P. R. China.
⁸ Laboratory of Omics Technology and Bioinformatics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, Sichuan Province, P. R. China. Electronic address: danxie@scu.edu.cn.

Abstract

Background: Using epigenetic markers and fragmentomics of cell-free DNA for cancer detection has been proven applicable.

Methods: We further investigated the diagnostic potential of combining two features (epigenetic markers and fragmentomic information) of cell-free DNA for detecting various types of cancers. To do this, we extracted cfDNA fragmentomic features from 191 whole-genome sequencing data and studied them in 396 low-pass 5hmC sequencing data, which included four common cancer types and control samples.

Results: In our analysis of 5hmC sequencing data from cancer samples, we observed aberrant ultra-long fragments (220-500 bp) that differed from normal samples in terms of both size and coverage profile. These fragments played a significant role in predicting cancer. Leveraging the ability to detect cfDNA hydroxymethylation and fragmentomic markers simultaneously in low-pass 5hmC sequencing data, we developed an integrated model that incorporated 63 features representing both fragmentomic features and hydroxymethylation signatures. This model achieved high sensitivity and specificity for pan-cancer detection (88.52% and 82.35%, respectively).

Conclusion: We showed that fragmentomic information in 5hmC sequencing data is an ideal marker for cancer detection and that it shows high performance in low-pass sequencing data.

Keywords: 5-Hydroxymethylcytosine sequencing; Liquid biopsy; Plasma cell-free DNA.