Deficient mismatch repair and RAS mutation in colorectal carcinoma patients: a retrospective study in Eastern China.

Xiangyan Zhang,Huamin Liu,Yujing Xiao,Wenwen Ran,Yujun Li,Xiaoming Xing,Xiaonan Wang,Jie Wu,Lili Wang,Hong Li

doi:10.7717/peerj.4341

Abstract

ObjectivesTo investigate the frequency and prognostic role of deficient mismatch repair (dMMR) and RAS mutation in Chinese patients with colorectal carcinoma.MethodsClinical and pathological information from 813 patients were reviewed and recorded. Expression of mismatch repair proteins was tested by immunohistochemistry. Mutation analyses for RAS gene were performed by real-time polymerase chain reaction. Correlations of mismatch repair status and RAS mutation status with clinicopathological characteristics and disease survival were determined.ResultsThe overall percentage of dMMR was 15.18% (121/797). The proportion of dMMR was higher in patients <50 years old (p < 0.001) and in the right side of the colon (p < 0.001). Deficient mismatch repair was also associated with mucinous production (p < 0.001), poor differentiation (p < 0.001), early tumor stage (p < 0.05) and bowel wall invasion (p < 0.05). The overall RAS mutation rate was 45.88%, including 42.56% (346/813) KRAS mutation and 3.69% (30/813) NRAS mutation (including three patients with mutations in both). KRAS mutation was significantly associated with mucinous production (p < 0.05), tumor stage (p < 0.05) and was higher in non-smokers (p < 0.05) and patients with a family history of colorectal carcinoma (p < 0.05). Overall, 44.63% (54/121) dMMR tumors harbored KRAS mutation, however, dMMR tumors were less likely to have NRAS mutation. Moreover, dMMR, KRAS and NRAS mutation were not prognostic factors for stage I–III colorectal carcinoma.ConclusionsThis study confirms that the status of molecular markers involving mismatch repair status and RAS mutation reflects the specific clinicopathological characteristics of colorectal carcinoma.

Highlights

Colorectal cancer (CRC) is the fourth most common cancer in China, with 331,300 new cases and 159,300 disease-related deaths in 2012 (Chen et al, 2016)
microsatellite instability (MSI) is caused by a deficient mismatch repair system, which leads to a high rate of mutations in repeat sequences and accounts for approximately 15% of all CRCs as well as virtually all Lynch syndrome (LS) patients (Geiersbach & Samowitz, 2011; Marra & Boland, 1995; Zhang et al, 2016)
Patients diagnosed with stage I–III colorectal carcinoma were used to explore the prognostic role of deficient mismatch repair (dMMR) and RAS mutation with disease-free survival (DFS) and overall survival (OS)

Summary

Introduction

Colorectal cancer (CRC) is the fourth most common cancer in China, with 331,300 new cases and 159,300 disease-related deaths in 2012 (Chen et al, 2016). Deficient mismatch repair and RAS mutation in colorectal carcinoma patients: a retrospective study in Eastern China. Microsatellite instability (MSI) and RAS mutation have been well studied as two prevalent genetic biomarkers involved in colorectal carcinogenesis. MSI is caused by a deficient mismatch repair (dMMR) system, which leads to a high rate of mutations in repeat sequences and accounts for approximately 15% of all CRCs as well as virtually all Lynch syndrome (LS) patients (Geiersbach & Samowitz, 2011; Marra & Boland, 1995; Zhang et al, 2016). Tumors with high level microsatellite instability (MSI-H) caused by germ line mutations or epigenetic silencing of MMR genes have unique clinicopathological characteristics (Cunningham et al, 2010). In early stage CRC, patients with MSI-H demonstrated favorable prognosis compared to those with low level of microsatellite instability (MSI-L) and microsatellite stability (MSS) (Ribic et al, 2003; Sinicrope et al, 2011), these patients did not benefit from fluoropyrimidine-based adjuvant chemotherapy (Ribic et al, 2003; Sargent et al, 2010)

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