Retrospective Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2015; 21(5): 1595-1605
Published online Feb 7, 2015. doi: 10.3748/wjg.v21.i5.1595
KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients
Ju-Xiang Ye, Yan Liu, Yun Qin, Hao-Hao Zhong, Wei-Ning Yi, Xue-Ying Shi
Ju-Xiang Ye, Yan Liu, Yun Qin, Hao-Hao Zhong, Xue-Ying Shi, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China
Wei-Ning Yi, Department of Epidemiology and Biostatistics, Peking University Health Science Center, Beijing 100191, China
Author contributions: Ye JX and Liu Y contributed equally to this work in writing and revising the manuscript; Qin Y collected the clinical and pathological information of cases in this study; Zhong HH contributed to KRAS and BRAF gene mutation analysis; Yi WN analyzed all the data; Shi XY designed the work and revised the manuscript.
Supported by Grant from the Xinjiang Uygur Autonomous Region Natural Science Fund, No. 201233146-14 (partly).
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: Xue-Ying Shi, MD, PhD, Associate Professor, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, No. 38 Xueyuan Road, Beijing 100191, China. shixueying@bjmu.edu.cn
Telephone: +86-10-82805488 Fax: +86-10-82801685
Received: July 17, 2014
Peer-review started: July 18, 2014
First decision: October 14, 2014
Revised: October 28, 2014
Accepted: December 8, 2014
Article in press: December 8, 2014
Published online: February 7, 2015
Abstract

AIM: To investigate gene mutations and DNA mismatch repair (MMR) protein abnormality in Chinese colorectal carcinoma (CRC) patients and their correlations with clinicopathologic features.

METHODS: Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded. Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used. Expression of MMR proteins including MHL1, MSH2, MSH6 and PMS2 was evaluated by immunohistochemistry. Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age, gender, cancer stage, location, and histology were analyzed. Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.

RESULTS: The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%, respectively. KRAS mutations were more common in patients ≥ 50 years old (39.8% vs 22% in patients < 50 years old, P < 0.05). The frequencies of BRAF mutants were higher in tumors from females (6.6% vs males 2.8%, P < 0.05), located in the right colon (9.6% vs 2.1% in the left colon, 1.8% in the rectum, P < 0.01), with mucinous differentiation (9.8% vs 2.8% without mucinous differentiation, P < 0.01), or being poorly differentiated (9.5% vs 3.4% well/moderately differentiated, P < 0.05). MMR deficiency was strongly associated with proximal location (20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum, P < 0.001), early cancer stage (15.0% in stages I-II vs 7.7% in stages III-IV, P < 0.05), and mucinous differentiation (20.2% vs 9.2% without mucin, P < 0.01). A higher frequency of MLH1/PMS2 loss was found in females (9.2% vs 4.4% in males, P < 0.05), and MSH2/MSH6 loss tended to be seen in younger (<50 years old) patients (12.0% vs 4.0% ≥ 50 years old, P < 0.05). MMR deficient tumors were less likely to have KRAS mutations (18.8% vs 41.7% in MMR proficient tumors, P < 0.05) and tumors with abnormal MLH1/PMS2 tended to harbor BRAF mutations (15.4% vs 4.2% in MMR proficient tumors, P < 0.05).

CONCLUSION: The frequency of sporadic CRCs having BRAF mutation, MLH1 deficiency and MSI in Chinese population may be lower than that in the Western population.

Keywords: Colorectal carcinoma, KRAS, BRAF, DNA mismatch repair, MLH1, MSH2, MSH6, PMS2

Core tip: Tests for KRAS, BRAF and DNA mismatch repair protein status were important for clinical management of patients with colorectal carcinoma (CRC). Investigations from large samples for these molecular markers were limited in Chinese CRC patients. In the present study, we collected and summarized clinicopathological and molecular data of 535 CRC patients in our institution. These results would help to understand CRC molecular features and guide Lynch syndrome screening, CRC clinical management and individualized therapy in the Chinese population.