Retrospective Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2015; 21(3): 926-934
Published online Jan 21, 2015. doi: 10.3748/wjg.v21.i3.926
Deficient DNA mismatch repair is associated with favorable prognosis in Thai patients with sporadic colorectal cancer
Krittiya Korphaisarn, Ananya Pongpaibul, Chanin Limwongse, Ekkapong Roothumnong, Wipawi Klaisuban, Akarin Nimmannit, Artit Jinawath, Charuwan Akewanlop
Krittiya Korphaisarn, Charuwan Akewanlop, Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok 10700, Thailand
Ananya Pongpaibul, Wipawi Klaisuban, Department of Pathology, Faculty of Medicine Siriraj Hospital, Bangkok 10700, Thailand
Chanin Limwongse, Ekkapong Roothumnong, Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok 10700, Thailand
Akarin Nimmannit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Bangkok 10700, Thailand
Artit Jinawath, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Bangkok 10400, Thailand
Author contributions: Korphaisarn K performed the research, acquired and analyzed the data, and drafted the manuscript; Pongpaibul A, Klaisuban W, Limwongse C, Roothumnong E and Jinawath A co-supervised the field activities; Nimmannit A designed the analysis strategy, and reviewed and edited manuscript; and Akewanlop C designed the study, supervised the study, critically revised the manuscript, and approved the final version for publication.
Supported by Siriraj Research Development Fund No. 459/2554(EC2).
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/
Correspondence to: Charuwan Akewanlop, MD, Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, 13th Floor Chalerm-Prakiat Building, Bangkok-noi, Bangkok 10700, Thailand. charuwan.ake@mahidol.ac.th
Telephone: +66-2-4197000 Fax: +66-2-4181788
Received: June 7, 2014
Peer-review started: June 8, 2014
First decision: June 27, 2014
Revised: July 30, 2014
Accepted: September 18, 2014
Article in press: September 19, 2014
Published online: January 21, 2015
Processing time: 227 Days and 1 Hours
Abstract

AIM: To determine the prognostic significance of deficient mismatch repair (dMMR) and BRAF V600E in Thai sporadic colorectal cancer (CRC) patients.

METHODS: We studied a total of 211 out of 405 specimens obtained from newly diagnosed CRC patients between October 1, 2006 and December 31, 2007 at Siriraj Hospital, Mahidol University. Formalin-fixed paraffin-embedded blocks of CRC tissue samples were analyzed for dMMR by detection of MMR protein expression loss by immunohistochemistry or microsatellite instability using polymerase chain reaction (PCR)-DHPLC. BRAF V600E mutational analysis was performed in DNA extracted from the same archival tissues by two-round allele-specific PCR and analyzed by high sensitivity DHPLC. Associations between patient characteristics, MMR and BRAF status with disease-free survival (DFS) and overall survival (OS) were determined by Kaplan-Meier survival plots and log-rank test together with Cox’s proportional hazard regression.

RESULTS: dMMR and BRAF V600E mutations were identified in 31 of 208 (14.9%) and 23 of 211 (10.9%) tumors, respectively. dMMR was more commonly found in patients with primary colon tumors rather than rectal cancer (20.4% vs 7.6%, P =0.01), but there was no difference in MMR status between the right-sided and left-sided colon tumors (20.8% vs 34.6%, P = 0.24). dMMR was associated with early-stage rather than metastatic disease (17.3% vs 0%, P = 0.015). No clinicopathological features such primary site or tumor differentiation were associated with the BRAF mutation. Six of 31 (19.3%) samples with dMMR carried the BRAF mutation, while 17 of 177 (9.6%) with proficient MMR (pMMR) harbored the mutation (P = 0.11). Notably, patients with dMMR tumors had significantly superior DFS (HR = 0.30, 95%CI: 0.15-0.77; P = 0.01) and OS (HR = 0.29, 95%CI: 0.10-0.84; P = 0.02) compared with patients with pMMR tumors. By contrast, the BRAF V600E mutation had no prognostic impact on DFS and OS.

CONCLUSION: The prevalence of dMMR and BRAF V600E in Thai sporadic CRC patients was 15% and 11%, respectively. The dMMR phenotype was associated with a favorable outcome.

Keywords: Sporadic colorectal cancer, Mismatch repair, BRAF, Overall survival

Core tip: This study is the first report of prevalence and outcome in sporadic colorectal cancer that habour deficient mismatch repair (dMMR) and BRAF gene mutation in Thai population. The prevalence of dMMR and BRAF V600E mutation was 15% and 11%, respectively. This study confirmed the favorable outcome in patients with dMMR tumors, which is consistent to the results of previous reports in Caucasian population. The method we used to detect BRAF mutation is allele specific polymerase chain reaction which has the highest sensitivity to detect this mutation when compared to previously reported methods.