Observational Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2020; 26(2): 184-198
Published online Jan 14, 2020. doi: 10.3748/wjg.v26.i2.184
Impact of GFRA1 gene reactivation by DNA demethylation on prognosis of patients with metastatic colon cancer
Wan-Ru Ma, Peng Xu, Zhao-Jun Liu, Jing Zhou, Lian-Kun Gu, Jun Zhang, Da-Jun Deng
Wan-Ru Ma, Zhao-Jun Liu, Jing Zhou, Lian-Kun Gu, Da-Jun Deng, Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100143, China
Peng Xu, Jun Zhang, Shihezi University School of Medicine, Shihezi 832000, Xinjiang Uygur Autonomous Region, China
Peng Xu, Morphological Center of Basic Medical School of Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China
Author contributions: Deng DJ and Zhang J designed the research; Ma WR, Xu P, Zhou J, and Gu LK performed the research; Ma WR and Liu ZJ analyzed the data; Ma WR, Xu P, Zhang J, and Deng DJ wrote the paper. Ma WR and Xu P contributed equally to this work. Zhang J is an equal corresponding author.
Supported by the National Natural Science Foundation of China A3 Foresight Program, No. 31261140372; Beijing Science and Technology Commission, No. Z151100001615022; and the Science Foundation of Peking University Cancer Hospital, No. 2017-25.
Institutional review board statement: This study was reviewed and approved by The Institutional Review Board of the Peking University Cancer Hospital and Institute.
Institutional review board statement: This study was reviewed and approved by The Institutional Review Board of the Peking University Cancer Hospital and Institute.
Informed consent statement: The patients were not required to give informed consent to the study because the analysis used anonymous data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The data and materials of the study are available from the corresponding author upon reasonable request.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: Da-Jun Deng, MD, Professor, Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China. dengdajun@bjmu.edu.cn
Received: October 8, 2019
Peer-review started: October 8, 2019
First decision: November 11, 2019
Revised: December 14, 2019
Accepted: December 21, 2019
Article in press: December 21, 2019
Published online: January 14, 2020
Processing time: 97 Days and 8.2 Hours
ARTICLE HIGHLIGHTS
Research background

The membrane receptor protein GFRA1 is normally expressed in neural cells in many organs, including the colon. The GFRA1 gene is abnormally and frequently expressed in cancer cells. Anti-GFRA1 autoantibodies can be detected in patients with breast cancer. Several preclinical anti-GFRA1 antibody-drug conjugates for breast cancer treatment have been developed.

Research motivation

Recently, we reported that the GFRA1 gene is reactivated by DNA demethylation in gastric cancer, which could be used to predict cancer metastasis. Because GFRA1 is normally expressed in neural cells in the colon, it is interesting to study whether GFRA1 reactivation by DNA demethylation is associated with colon cancer (CC) progression and can be used as a therapy target.

Research objectives

To study whether abnormal GFRA1 demethylation is a driver for CC metastasis and the membrane protein GFRA1 is a potential therapeutic target.

Research methods

CC tissues from 144 patients were included in this study. The level of GFRA1 demethylation was analyzed by quantitative methylation-specific PCR and bisulfite-sequencing. A set of in vitro and in vivo experimental assays were used to evaluate the effect of abnormal GFRA1 expression on CC development.

Research results

The level of GFRA1 demethylated alleles was significantly increased during CC development and positively associated with poor CC differentiation, distant CC metastasis, and short OS of CC patients. GFRA1 overexpression significantly promoted CC cell proliferation and invasion in vitro and CC growth in nude mice.

Research conclusions

GFRA1 is frequently reactivated by DNA demethylation in CC tissues. GFRA1 demethylation may be a driver for CC development. GFRA1 protein might be a therapeutic target for CC patients, especially those with metastatic potential.

Research perspectives

A prospective study is expected to confirm our present findings. It is worth further studying whether dysfunctions of the GFRA1 protein by antibody could prevent CC metastasis.