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
Processing time: 123 Days and 6.6 Hours
Abstract
BACKGROUND

Genomic profiling of tumors has contributed to the understanding of colorectal cancer (CRC), facilitating diagnosis, prognosis and selection of treatments, including targeted regimens. A report suggested that a 19-gene-based risk classifier (TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging.

AIM

To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology.

METHODS

A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival (PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction (qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry (IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro.

RESULTS

In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen (P = 0.041). In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7 (SLAMF7) and triggering receptor expressed on myeloid cells 1 (TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR, and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD 73 were significantly lower at day 5 of co-culture than at day 0.

CONCLUSION

The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.

Keywords: Colorectal cancer; Prognosis; Immunotherapy; Signaling lymphocytic activation molecule family, member 7; Triggering receptor expressed on myeloid cells 1

Core tip: The current study showed that in the patients with stage IV colorectal cancer (CRC) and a higher 19-gene based risk classifier score, the target-regimen-specific progression-free survival (PFS) was significantly increased compared with the 5-fluorouracil-regimen-specific PFS. Using another 10 validate set, down-regulation of signaling lymphocytic activation molecule family, member 7 (SLAMF7) and up-regulation of triggering receptor expressed on myeloid cells 1 were identified in primary and metastatic tumors compared with normal tissue. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD68 and CD73 were significantly lower at day 5 of co-culture than at day 0.