Observational Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2015; 21(4): 1275-1283
Published online Jan 28, 2015. doi: 10.3748/wjg.v21.i4.1275
Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer
Shigenori Kadowaki, Miho Kakuta, Shuhei Takahashi, Akemi Takahashi, Yoshiko Arai, Yoji Nishimura, Toshimasa Yatsuoka, Akira Ooki, Kensei Yamaguchi, Keitaro Matsuo, Kei Muro, Kiwamu Akagi
Shigenori Kadowaki, Akira Ooki, Kensei Yamaguchi, Division of Gastroenterology, Saitama Cancer Center, Saitama 362-0806, Japan
Miho Kakuta, Shuhei Takahashi, Akemi Takahashi, Yoshiko Arai, Kiwamu Akagi, Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan
Yoji Nishimura, Toshimasa Yatsuoka, Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama 362-0806, Japan
Keitaro Matsuo, Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan
Shigenori Kadowaki, Kei Muro, Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi 464-8681, Japan
Author contributions: Kadowaki S, Matsuo K and Akagi K designed the study, analyzed the data, interpreted the results and wrote the paper; Kakuta M, Takahashi S, Takahashi A, Arai Y and Akagi K carried out all the laboratory experiments; Kadowaki S, Kakuta M, Ooki A, Nishimura Y, Yatsuoka T and Akagi K collected the data; Yamaguchi K and Muro K supervised this study; and all authors have read and approved the manuscript.
Supported by Japanese Ministry of Health, Labor and Welfare.
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: Kiwamu Akagi, MD, PhD, Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan. akagi@cancer-c.pref.saitama.jp
Telephone: +81-48-7221111 Fax: +81-48-7235197
Received: June 19, 2014
Peer-review started: June 20, 2014
First decision: July 21, 2014
Revised: September 9, 2014
Accepted: October 14, 2014
Article in press: October 15, 2014
Published online: January 28, 2015
Processing time: 222 Days and 4.5 Hours
Abstract

AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability (MSI) status in Japanese colorectal cancer (CRC) population.

METHODS: We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected, stage I-III CRC and examined associations of these mutations with disease-free survival (DFS) and overall survival (OS) using uni- and multivariate Cox proportional hazards models.

RESULTS: KRAS and BRAF mutations were detected in 312 (38%) of 812 and 40 (5%) of 811 tumors, respectively. KRAS mutations occurred more frequently in females than in males (P = 0.02), while the presence of BRAF mutations was significantly associated with the female gender (P = 0.006), proximal tumor location (P < 0.001), mucinous or poorly differentiated histology (P < 0.001), and MSI-high tumors (P < 0.001). After adjusting for relevant variables, including MSI status, KRAS mutations were associated with poorer DFS (HR = 1.35; 95%CI: 1.03-1.75) and OS (HR = 1.46; 95%CI: 1.09-1.97). BRAF mutations were poor prognostic factors for DFS (HR = 2.20; 95%CI: 1.19-4.06) and OS (HR = 2.30; 95%CI: 1.15-4.71). Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS.

CONCLUSION: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, in Japanese patients with curatively resected CRC.

Keywords: Colorectal cancer; KRAS; BRAF; Microsatellite instability; Prognostic factor

Core tip: Although KRAS and BRAF mutations play a critical role in colorectal cancer development, little is known regarding the prognostic role of these genetic alterations after adjustment for microsatellite instability status in Asian populations. To the authors’ knowledge, the current study is the first large-scale study to clarify the impact of KRAS and BRAF mutations on the survival outcomes of colorectal cancer in Asian populations. We found that KRAS and BRAF mutations were separately associated with inferior disease-free survival and overall survival, independent of microsatellite instability status, in patients with curatively resected colorectal cancer.