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
Abstract
BACKGROUND

The development of colorectal cancer (CRC) is a complicated multistep process that involves an accumulation of mutations in tumor suppressor genes and oncogenes. In the process of DNA replication, base mismatch often occurs due to various factors leading to abnormal expression of mismatch repair genes (MMR), among which MLH1 and MSH2 are the most important. Recently, numerous studies indicated that MLH1/MSH2 phenotype is associated with CRC. We wanted to elucidate the role of MLH1/MSH2 in the prediction and prognosis of CRC through long-term clinical observation.

AIM

To evaluate the prognostic and predictive significance of MLH1/MSH2 in patients with stage II-III CRC using immunohistochemical analysis and GeneScan.

METHODS

Specimens from 681 patients with CRC (395 stage II and 286 stage III, 387 males and 294 females) who underwent curative surgical resection from 2013 to 2016 were tested. Immunohistochemistry was used to analyze MMR status and the microsatellite status of 133 patients was determined by GeneScan analysis.

RESULTS

Five hundred and fifty (80.76%) patients were MLH1/MSH2 positive and 131 (19.24%) were negative by immunohistochemistry. MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and had poor differentiation and less mucin production (P < 0.05). Patients of different groups 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). Univariate and multivariate analyses demonstrated MLH1/MSH2 expression as an independent prognostic and predictive factor for stage II/III CRC. MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio (HR) = 4.064, 95%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). However, patients with stage II disease or MLH1/MSH2-positive patients with stage III disease did not benefit from adjuvant chemotherapy. GeneScan analysis demonstrated that among 133 patients, 105 (78.95%) were microsatellite stable, and 28 (21.05%) had microsatellite instability (MSI), including 18 (13.53%) with high MSI and 10 (7.52%) with low MSI. This is consistent with the immunohistochemical results.

CONCLUSION

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.

Keywords: Colorectal cancer, Mismatch repair gene, MLH1, MSH2, Microsatellite instability

Core tip: Mutation or methylation of mismatch repair gene leads to microsatellite instability (MSI), which is one of the most important mechanisms for the development of colorectal cancer (CRC). The purpose of this study was to collect data on MLH1/MSH2 phenotype and MSI status in stage II-III CRC patients and to assess their predictive and prognostic value. This is the first large study in China to evaluate the role of MLH1/MSH2 in CRC and its relationship with adjuvant chemotherapy.