Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Mar 15, 2022; 14(3): 690-702
Published online Mar 15, 2022. doi: 10.4251/wjgo.v14.i3.690
Cost-effective low-coverage whole-genome sequencing assay for the risk stratification of gastric cancer
Li-Ping Ye, Xin-Li Mao, Xian-Bin Zhou, Yi Wang, Shi-Wen Xu, Sai-Qin He, Zi-Liang Qian, Xiao-Gang Zhang, Li-Juan Zhai, Jin-Bang Peng, Bin-Bin Gu, Xiu-Xiu Jin, Ya-Qi Song, Shao-Wei Li
Li-Ping Ye, Xin-Li Mao, Xian-Bin Zhou, Yi Wang, Sai-Qin He, Jin-Bang Peng, Bin-Bin Gu, Xiu-Xiu Jin, Shao-Wei Li, Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
Li-Ping Ye, Xin-Li Mao, Xian-Bin Zhou, Yi Wang, Sai-Qin He, Jin-Bang Peng, Bin-Bin Gu, Xiu-Xiu Jin, Shao-Wei Li, Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
Li-Ping Ye, Xin-Li Mao, Xian-Bin Zhou, Yi Wang, Sai-Qin He, Jin-Bang Peng, Bin-Bin Gu, Xiu-Xiu Jin, Shao-Wei Li, Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
Shi-Wen Xu, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
Zi-Liang Qian, Suzhou Hongyuan Biotech Inc., Suzhou 215000, Zhejiang Province, China
Zi-Liang Qian, Prophet Genomics Inc., California, CA 95101, United States
Xiao-Gang Zhang, Catcher Bio Inc., Hangzhou 310000, Zhejiang Province, China
Li-Juan Zhai, Department of Medicine, Catcher Bio Inc., Hangzhou 310000, Zhejiang Province, China
Ya-Qi Song, Taizhou Hospital of Zhejiang Province, Zhejiang University School of Medicine, Linhai 317000, Zhejiang Province, China
Author contributions: Zhou XB, Wang Y, He SQ, Zhang XG, Zhai LJ, Peng JB, Gu BB, Jin XX, Song YQ, and Ye LP participated in the design of the study and performed the statistical analysis; Mao XL, Xu SW, Qian ZL, and Li SW drafted the manuscript. All authors read and approved the final manuscript.
Supported by Program of Taizhou Science and Technology Grant, No. 20ywb29; Medical Health Science and Technology Project of Zhejiang Province, No. 2021PY083; Key Technology Research and Development Program of Zhejiang Province, No. 2019C03040; Open Project Program of Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, No. 21SZDSYS01 and 21SZDSYS09; and Major Research Program of Taizhou Enze Medical Center Grant, No. 19EZZDA2.
Institutional review board statement: The study was reviewed and approved by the the Institutional Ethics Committee of Taizhou Hospital of Zhejiang Province (Approval No. K20201205).
Conflict-of-interest statement: Author Qian ZL was employed by the company Suzhou Hongyuan Biotech Inc., and Zhang XG and Zhai LJ were employed by the company Catcher Bio Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at li_shaowei81@hotmai.com.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Shao-Wei Li, PhD, Academic Fellow, Assistant Professor, Associate Research Scientist, Instructor, Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No. 150 Xinmen Street, Linhai 317000, Zhejiang Province, China. li_shaowei81@hotmail.com
Received: August 10, 2021
Peer-review started: August 10, 2021
First decision: December 4, 2021
Revised: December 25, 2021
Accepted: February 22, 2022
Article in press: February 22, 2022
Published online: March 15, 2022
Processing time: 212 Days and 4.1 Hours
Abstract
BACKGROUND

Gastric cancer (GC), a multifactorial disease, is caused by pathogens, such as Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), and genetic components.

AIM

To investigate microbiomes and host genome instability by cost-effective, low-coverage whole-genome sequencing, as biomarkers for GC subtyping.

METHODS

Samples from 40 GC patients were collected from Taizhou Hospital, Zhejiang Province, affiliated with Wenzhou Medical University. DNA from the samples was subjected to low-coverage whole-genome sequencing with a median genome coverage of 1.86 × (range: 1.03 × to 3.17 ×) by Illumina × 10, followed by copy number analyses using a customized bioinformatics workflow ultrasensitive chromosomal aneuploidy detector.

RESULTS

Of the 40 GC samples, 20 (50%) were found to be enriched with microbiomes. EBV DNA was detected in 5 GC patients (12.5%). H. pylori DNA was found in 15 (37.5%) patients. The other 20 (50%) patients were found to have relatively higher genomic instability. Copy number amplifications of the oncogenes, ERBB2 and KRAS, were found in 9 (22.5%) and 7 (17.5%) of the GC samples, respectively. EBV enrichment was found to be associated with tumors in the gastric cardia and fundus. H. pylori enrichment was found to be associated with tumors in the pylorus and antrum. Tumors with elevated genomic instability showed no localization and could be observed in any location. Additionally, H. pylori-enriched GC was found to be associated with the Borrmann type II/III and gastritis history. EBV-enriched GC was not associated with gastritis. No statistically significant correlation was observed between genomic instability and gastritis. Furthermore, these three different molecular subtypes showed distinct survival outcomes (P = 0.019). EBV-positive tumors had the best prognosis, whereas patients with high genomic instability (CIN+) showed the worst survival. Patients with H. pylori infection showed intermediate prognosis compared with the other two subtypes.

CONCLUSION

Thus, using low-coverage whole-genome sequencing, GC can be classified into three categories based on disease etiology; this classification may prove useful for GC diagnosis and precision medicine.

Keywords: Gastric cancer; Whole-genome sequencing; Helicobacter pylori infections; Epstein-Barr virus infections; Genetic components; Precision medicine

Core Tip: This study investigated the microbiomes and host genome instability via cost-effective low-coverage whole-genome sequencing, to establish the findings for consideration in the development of a biomarker for gastric cancer (GC) subtyping. We believe that our study makes a significant contribution to the literature because it identified three different GC subtypes in the Chinese population, and these were related to different tumorigenesis mechanisms, chronic Epstein-Barr virus infection, Helicobacter pylori infections, and chromosomal instabilities. This discovery may therefore provide guidance for conducting future studies to realize GC treatment and prevention.