Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Jun 16, 2021; 9(17): 4143-4158
Published online Jun 16, 2021. doi: 10.12998/wjcc.v9.i17.4143
Why MUC16 mutations lead to a better prognosis: A study based on The Cancer Genome Atlas gastric cancer cohort
Yu-Jie Huang, Zhi-Fei Cao, Jie Wang, Jian Yang, Yi-Jun Wei, Yu-Chen Tang, Yin-Xiang Cheng, Jian Zhou, Zi-Xiang Zhang
Yu-Jie Huang, Jie Wang, Jian Yang, Yi-Jun Wei, Yu-Chen Tang, Yin-Xiang Cheng, Jian Zhou, Zi-Xiang Zhang, Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
Zhi-Fei Cao, Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
Author contributions: Huang YJ and Cao ZF contributed equally to this work; Huang YJ and Cao ZF were responsible for conceptualization, data curation, methodology, and wrote the original draft; Wang J, Yang J, Wei YJ, Tang YC, Cheng YX and Zhou J were responsible for visualization and software; Zhang ZX was responsible for validation, supervision, reviewed and edited the manuscript; all authors approved the final submission.
Supported by National Natural Science Foundation of China, No. 81902385; The Project of Suzhou People's Livelihood Science and Technology, No. SYS2018037 and No. SYS201739; The Six Talent Peaks Project in Jiangsu Province, No. WSW-059; Postgraduate Research & Practice Innovation Program of Jiangsu Province, No. SJCX20_1073; Medical Research Programs of Health Commission Foundation of Jiangsu Province, No. H2019071; and The Project of Medical Research of Jiangsu Province, No. Y2018094 and No. H2018056.
Institutional review board statement: This study was a bioinformatics study, and the data used was downloaded from a public database, so the study did not require the approval of the ethics committee.
Informed consent statement: This research did not involve any human or animal experiments, and the data used was downloaded from a public database, so the study did not require the informed consent.
Conflict-of-interest statement: None declared.
Data sharing statement: No additional data are available.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zi-Xiang Zhang, PhD, Associate Professor, Department of General Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215006, Jiangsu Province, China. zixiangzhang@163.com
Received: December 28, 2020
Peer-review started: December 28, 2020
First decision: January 17, 2021
Revised: January 25, 2021
Accepted: March 5, 2021
Article in press: March 5, 2021
Published online: June 16, 2021
Abstract
BACKGROUND

MUC16, encoding cancer antigen 125, is a frequently mutated gene in gastric cancer. In addition, MUC16 mutations seem to result in a better prognosis in gastric cancer. However, the mechanisms that lead to a better prognosis by MUC16 mutations have not yet been clarified.

AIM

To delve deeper into the underlying mechanisms that explain why MUC16 mutations signal a better prognosis in gastric cancer.

METHODS

We used multi-omics data, including mRNA, simple nucleotide variation, copy number variation and methylation data from The Cancer Genome Atlas, to explore the relationship between MUC16 mutations and prognosis. Cox regression and random survival forest algorithms were applied to search for hub genes. Gene set enrichment analysis was used to elucidate the molecular mechanisms. Single-sample gene set enrichment analysis and “EpiDISH” were used to assess immune cells infiltration, and “ESTIMATE” for analysis of the tumor microenvironment.

RESULTS

Our study found that compared to the wild-type group, the mutation group had a better prognosis. Additional analysis indicated that the MUC16 mutations appear to activate the DNA repair and p53 pathways to act as an anti-tumor agent. We also identified a key gene, NPY1R (neuropeptide Y receptor Y1), which was significantly more highly expressed in the MUC16 mutations group than in the MUC16 wild-type group. The high expression of NPY1R predicted a poorer prognosis, which was also confirmed in a separate Gene Expression Omnibus cohort. Further susceptibility analysis revealed that NPY1R might be a potential drug target for gastric cancer. Furthermore, in the analysis of the tumor microenvironment, we found that immune cells in the mutation group exhibited higher anti-tumor effects. In addition, the tumor mutation burden and cancer stem cells index were also higher in the mutation group than in the wild-type group.

CONCLUSION

We speculated that the MUC16 mutations might activate the p53 pathway and DNA repair pathway: alternatively, the tumor microenvironment may be involved.

Keywords: Gastric cancer, MUC16 mutation, Cancer antigen 125, Prognosis, The Cancer Genome Atlas, Gene Expression Omnibus

Core Tip: Our study utilized multi-omics data from The Cancer Genome Atlas, by analyzing these data, we found that the MUC16 mutations may activate the p53 pathway and DNA repair pathway on the one hand, on the other hand, the tumor microenvironment may be involved, with higher tumor killer cells and lower stromal score together building the unique tumor microenvironment of the mutation group.