Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2019; 25(11): 1341-1354
Published online Mar 21, 2019. doi: 10.3748/wjg.v25.i11.1341
Clinical assessment and identification of immuno-oncology markers concerning the 19-gene based risk classifier in stage IV colorectal cancer
Jong Lyul Lee, Seon Ae Roh, Chan Wook Kim, Yi Hong Kwon, Ye Jin Ha, Seon-Kyu Kim, Seon-Young Kim, Dong-Hyung Cho, Yong Sung Kim, Jin Cheon Kim
Jong Lyul Lee, Chan Wook Kim, Jin Cheon Kim, Department of Surgery, University of Ulsan College of Medicine, Seoul 05505, South Korea
Jong Lyul Lee, Seon Ae Roh, Chan Wook Kim, Yi Hong Kwon, Ye Jin Ha, Jin Cheon Kim, Institute of Innovative Cancer Research, Asan Medical Center, Seoul 05505, South Korea
Seon-Kyu Kim, Seon-Young Kim, Yong Sung Kim, Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea
Dong-Hyung Cho, School of Life Sciences, Kyungpook National University 80 Daehak-ro, Daegu 41566, South Korea
Author contributions: Lee JL, Roh SA and Kim JC made substantial contributions to the study conception and design, data acquisition, analysis, and interpretation, drafting a critical revision of the manuscript, and approving the final version of the text. Lee JL and Roh SA contributed equally. Kim CW made contributions to the study design, provided data from his patients, and approved the final version of the text. Kwon YH performed research, helped to write parts of the manuscript related to method, and approved the final version of the text. Ha YJ performed research and approved the final version of the text. Kim SK made contributions to the study design and helped to analyze data. Kim SY made contributions to the study design and helped to analyze data. Cho DH made substantial contributions to the study conception and interpretation. Kim YS made substantial contributions to the study conception and design, drafting a revision of the manuscript.
Supported by Korea Research Foundation, No. 2016R1E1A1A02919844 to Kim JC and No. 2017R1A2B1009062 to Roh SA; Ministry of Science, ICT, and Future Planning, Republic of Korea and the Asan Institute for Life Sciences, No. 2016-710 to Lee JL.
Institutional review board statement: The study protocol was approved by the Institutional Review Board of Asan Medical Center (registration No. 2015-0581), in accord with the Declaration of Helsinki.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The ARRIVE Guidelines have been adopted.
Open-Access: This 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 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: Jin Cheon Kim, MD, PhD, Doctor, Professor, Surgeon, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea. jckim@amc.seoul.kr
Telephone: +82-2-30103489 Fax: +82-2-4749027
Received: November 20, 2018
Peer-review started: November 20, 2018
First decision: January 30, 2019
Revised: February 19, 2019
Accepted: February 22, 2019
Article in press: February 22, 2019
Published online: March 21, 2019
ARTICLE HIGHLIGHTS
Research background

Our team previously developed a risk score system based a 19 gene-based scoring system (TCA19), worked as a prognostic factor in stage II-III colorectal cancer (CRC). Stage IV CRC is still challenging in the treatment including target-regimen and immunotherapy.

Research motivation

It is needed to identify whether the TCA19 scores predict survival outcomes in patients with stage IV CRC undergoing different chemotherapy regimens including target-regimen and 19 genes are related to immuno-oncology.

Research objectives

The current study aims to determine whether the TCA19 system can be used as a prognostic indicator for stage IV CRC and to identify possible target or marker genes associated with immune functions from 19 genes.

Research methods

A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinico-pathologic variables, and progression-free survival (PFS). TCA19 gene expressions were determined by real-time quantitative polymerase chain reaction (RT-qPCR) in matched normal, primary tumor, and metastatic tumor tissues taken from the 60 study cohort. After selection of genes, related to immuno-oncology, expression of potential target or marker genes were examined by RT-qPCR, immunohistochemistry, western blot, and immunofluorescence staining using tissues from 10 validate set and in CRC cell lines co-cultured with monocytes in vitro.

Research results

In the patients with higher TCA19 score, the PFS rates of the patients with target-regimen were significantly higher than the patients with 5-fluorouracil-based regimen. In multivariable analysis, expression of signaling lymphocytic activation molecule family, member 7 (SLAMF7) and triggering receptor expressed on myeloid cells 1 (TREM1) was associated with PFS. From the results of the 10 validate set, down-regulation of SLAMF7 and up-regulation of TREM1 were observed in primary tumor and metastatic tumor tissues compared with normal tissue. In CRC cells expressing SLAMF7 that co-cultured with a monocytic cell line, levels of CD68 and CD73 in IFS imaging were significantly lower at day 5 of co-culture than at day 0. This result suggests that SLAMF7 may have an inhibitory role in the immune response.

Research conclusions

TCA19 system may be used as a prognostic indicator for stage IV CRC in terms of use of target-regimen. SLAMF7 and TREM1 may be related to tumorigenesis and progression according to down-regulation of SLAMF7 and up-regulation of TREM1 in tumor tissue.

Research perspectives

The current study found an inhibitory role of the SLAMF7 in the immune response. Recently, it is known that the patients with microsatellite-high CRC may respond the immune therapy. In this concept, the direction of the future research is the role of SLAMF7 in the patients with stage IV CRC in terms of the immune therapy.