Observational Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2019; 11(11): 1065-1080
Published online Nov 15, 2019. doi: 10.4251/wjgo.v11.i11.1065
Clinical significance of MLH1/MSH2 for stage II/III sporadic colorectal cancer
Shui-Ming Wang, Bin Jiang, Youping Deng, Shu-Liang Huang, Ming-Zhi Fang, Yu Wang
Shui-Ming Wang, Bin Jiang, National Center of Colorectal Disease, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
Youping Deng, Yu Wang, Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, United States
Shu-Liang Huang, Department of Pathology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
Ming-Zhi Fang, Yu Wang, Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
Author contributions: Wang SM and Wang Y performed the study and drafted the manuscript; Jiang B and Deng YP designed the study; Huang SL performed the experiments; Fang MZ enrolled the patients and acquired the follow-up data; Jiang B coordinated the study and analyzed the data; all the authors contributed to, read, and approved the final manuscript.
Supported by Medical Science and Technology Development Foundation, Nanjing Department of Health, No. YKK14140 (to Shui-Ming Wang) and No. ZKX15040 (to Bin Jiang); Project of Administration of Traditional Chinese Medicine of Jiangsu Province of China, No. LZ11101 (to Zhi-Ming Fang).
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine.
Informed consent statement: All participants provided informed consent prior to study enrollment.
Conflict-of-interest statement: All authors have no conflict of interest to disclose.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement checklist of items, and the manuscript was prepared and revised 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: Yu Wang, MD, PhD, Chief Doctor, Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China christinewangyu@outlook.com
Telephone: +86-17327005861 Fax: +86-25-627364
Received: April 29, 2019
Peer-review started: May 9, 2019
First decision: July 31, 2019
Revised: August 10, 2019
Accepted: September 10, 2019
Article in press: September 10, 2019
Published online: November 15, 2019
Processing time: 201 Days and 0 Hours
ARTICLE HIGHLIGHTS
Research background

Colorectal cancer (CRC) can arise through three distinct mutational pathways: Microsatellite instability, chromosomal instability, and CpG island methylator phenotype. We tested the hypothesis that CRC arising from the microsatellite-instability pathway through MLH1/MSH2-negative expression can lead a more favorable overall survival (OS) than MLH1/MSH2-positive patients. We also made an in-depth observation of the correlation between adjuvant chemotherapy and MLH1/MSH2 expression in different stages of CRC.

Research motivation

A larger sample size with a longer follow-up period was included to assess the effect of MLH1/MSH2 status on the prediction and prognosis of stage II-III CRC and its association with adjuvant chemotherapy. It is important for clinical doctors to choose optimal treatment regimen, especially adjuvant chemotherapy, for patients.

Research objectives

To evaluate the predictive and prognostic effects of MLH1/MSH2 status in stage II-III CRC patients and its significance in guiding adjuvant chemotherapy.

Research methods

We analyzed 681 postoperative patients with CRC with a median follow-up period of 56 mo (range, 8.0–72.0 mo) between January 2013 and December 2016. The main outcome data included MLH1/MSH2-positive rate, MLH1/MSH2-negative rate, and long-term follow-up outcomes.

Research results

The outcomes showed that 550 patients were MLH1/MSH2-positive and 131 were MLH1/MSH2-negative. MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and with poor differentiation and less mucin production (P < 0.05). Patients did not differ in terms of age, gender, tumor size, tumor stage, lymphocytic infiltration, or circumscribed margin. MLH1/MSH2-negative patients had a more favorable OS than MLH1/MSH2-positive patients (P < 0.001). In both stages II and III, MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio (HR) = 4.064, 95% confidence interval (CI): 2.241–7.369]. Adjuvant chemotherapy had a greater correlation with survival advantage in MLH1/MSH2-negative patients with stage III disease (P < 0.001, HR = 7.660, 95%CI: 2.974–15.883). Patients with stage II disease or MLH1/MSH2-positive stage III patients did not benefit from adjuvant chemotherapy.

Research conclusions

MLH1/MSH2 phenotype constitutes a pathologically and clinically distinct subtype of sporadic CRC. MLH1/MSH2 is an independent prognostic and predictive factor for outcome of stage II-III CRC.

Research perspectives

Our study demonstrated mismatch repair (MMR) is an important prognostic and predictive biomarker for stage II-III CRC, but we did not enroll the patients who used any PD-1/PD-L1 blocking therapy and had no data for survival improvement with different MMR statuses. In addition to detecting MMR status and tumor mutational burden, are there any indicators that are more sensitive to immunotherapy? The currently found immunologic drugs are only effective for high microsatellite instability (MSI-H)/dMMR population, but are ineffective for most patients with microsatellite stability (MSS). Would any new effective immune drugs be found for MSS patients? Is it possible to subdivide MSI-H (through the number of mutation sites) for enriching the dominant population in future? These issues will be the focal points and difficulty in our later research.