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. 2018 Sep 26:10:3911-3929.
doi: 10.2147/CMAR.S169649. eCollection 2018.

Prognostic value of the combination of microsatellite instability and BRAF mutation in colorectal cancer

Yingchi Yang  1 , Dong Wang  1 , Lan Jin  1 , Guocong Wu  1 , Zhigang Bai  1 , Jin Wang  1 , Hongwei Yao  1 , Zhongtao Zhang  1
Affiliations

Prognostic value of the combination of microsatellite instability and BRAF mutation in colorectal cancer

Yingchi Yang et al. Cancer Manag Res. .

Abstract

Purpose: The aim of this study was to investigate the prognostic value of the combination of microsatellite instability (MSI) and BRAF V600E mutation in colorectal cancer (CRC).

Materials and methods: We compare the prognosis difference among CRC patients with four subtypes according to MSI and BRAF mutation, ie, microsatellite stable/BRAF wild type (MSS/BRAFwt), MSS/BRAF mutation (MSS/BRAFmut), MSI/BRAFwt, and MSI/BRAFmut, by pooling the previous related reports and public available data sets till December 2017 for the first time.

Results: Twenty-seven independent studies comprising 24,067 CRC patients were included. Meta-analysis suggested that, compared with MSS/BRAFwt subtype, MSS/BRAFmut was associated with shorter overall survival (OS) (N=25, HR = 2.018, 95% CI = 1.706-2.388, P=2.220E-16), while there was a trend of association of MSI/BRAFmut with OS (N=13, HR = 1.324, 95% CI = 0.938-1.868, P=1.096E-01) and no association of MSI/BRAFwt with OS (N=17, HR = 0.996, 95% CI = 0.801-1.240, P=9.761E-01). Compared with MSI/ BRAFwt subtype, MSI/BRAFmut was a poor factor for OS (N=22, HR = 1.470, 95% CI = 1.243-1.740, P=7.122E-06). Compared with MSS/BRAFmut subtype, both MSI/BRAFwt (N=11, HR = 0.560, 95% CI = 0.433-0.725, P=1.034E-05) and MSI/BRAFmut (N=16, HR = 0.741, 95% CI = 0.567-0.968, P=2.781E-02) were favorable for OS. Subgroup analysis revealed similar results in all subgroups except the subgroup of stage IV cancer, in which MSI showed poor effects on OS in BRAF wild-type patients (N=6, HR = 1.493, 95% CI = 1.187-1.879, P=6.262E-04) but not in BRAF-mutated patients (N=5, HR = 1.143, 95% CI = 0.789-1.655, P=4.839E-01). Meta-analysis regression and test of interaction revealed no interaction of MSI with BRAF mutation when evaluating the associations of MSI/BRAF mutation subtypes with OS in CRC.

Conclusion: Among the four subtypes according to MSI and BRAF mutation, MSS/BRAFmut was a poor prognostic factor, while MSS/BRAFwt and MSI/BRAFwt were comparable and favorable and MSI/BRAFmut was moderate in CRC. The combination of MSI/BRAF mutations could facilitate the planning of individualized treatment strategies and prognosis improvement in CRC.

Keywords: BRAF mutation; colorectal cancer; meta-analysis; microsatellite instability; prognosis.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flow chart of study selection. Abbreviations: MSI, microsatellite instability; GEO, Gene Expression Omnibus; TCGA, The Cancer Genome Atlas; MSImut, microsatellite instability and BRAF mutation; MSIwt, microsatellite instability and BRAF wild type; MSSmut, microsatellite stable and BRAF mutation; MSSwt, microsatellite stable and BRAF wild type; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival.
Figure 2
Figure 2
Effect of MSI/BRAF mutation status on RFS and OS in colon cancer (GSE39582). Note: RFS (A) and OS (B) were compared among the colon cancer patients with four subtypes according to the combination of MSI and BRAF mutation, ie, MSSwt, MSSmut, MSIwt, and MSImut. Abbreviations: MSI, microsatellite instability; MSImut, microsatellite instability and BRAF mutation; MSIwt, microsatellite instability and BRAF wild type; MSSmut, microsatellite stable and BRAF mutation; MSSwt, microsatellite stable and BRAF wild type; RFS, recurrence-free survival; OS, overall survival.
Figure 3
Figure 3
Forest plot for MSI/BRAF mutation status and RFS in colorectal cancer. Notes: The colorectal cancer was divided into four subtypes according to the combination of MSI and BRAF mutation, ie, MSSwt, MSSmut, MSIwt, and MSImut. RFS was compared between MSSmut and MSSwt (A), MSIwt and MSSwt (B), MSImut and MSSwt (C), and MSImut and MSSmut (D) by pooling the previous studies. Abbreviations: MSImut, microsatellite instability and BRAF mutation; MSIwt, microsatellite instability and BRAF wild type; MSSmut, microsatellite stable and BRAF mutation; MSSwt, microsatellite stable and BRAF wild type; RFS, recurrence-free survival.
Figure 4
Figure 4
Forest plot for MSI/BRAF mutation status and PFS in colorectal cancer. Notes: The colorectal cancer was divided into four subtypes according to the combination of MSI and BRAF mutation, ie, MSSwt, MSSmut, MSIwt, and MSImut. PFS was compared between MSSmut and MSSwt (A), MSIwt and MSSwt (B), MSImut and MSIwt (C), and MSImut and MSSmut (D) by pooling the previous studies. Abbreviations: MSI, microsatellite instability; MSImut, microsatellite instability and BRAF mutation; MSIwt, microsatellite instability and BRAF wild type; MSSmut, microsatellite stable and BRAF mutation; MSSwt, microsatellite stable and BRAF wild type; PFS, progression-free survival.
Figure 5
Figure 5
Forest plot for MSI/BRAF mutation status and OS in colorectal cancer. Notes: The colorectal cancer was divided into four subtypes according to the combination of MSI and BRAF mutation, ie, MSSwt, MSSmut, MSIwt, and MSImut. OS was compared between MSSmut and MSSwt (A), MSImut and MSIwt (B), MSImut and MSSmut (C), MSIwt and MSSwt (D), MSImut and MSSwt (E), and MSIwt and MSSmut (F) by pooling the previous studies. Abbreviations: MSI, microsatellite instability; MSImut, microsatellite instability and BRAF mutation; MSIwt, microsatellite instability and BRAF wild type; MSSmut, microsatellite stable and BRAF mutation; MSSwt, microsatellite stable and BRAF wild type; OS, overall survival.
Figure 6
Figure 6
Begg’s funnel plot for the publication bias analysis for associations of MSI/BRAF mutation status with OS in colorectal cancer. Notes: The colorectal cancer was divided into four subtypes according to the combination of MSI and BRAF mutation, ie, MSSwt, MSSmut, MSIwt, and MSImut. Potential publication bias was explored by Begg’s funnel plots for OS comparison between MSSmut and MSSwt (A), MSIwt and MSSwt (B), MSImut and MSSwt (C), MSImut and MSIwt (D), MSIwt and MSSmut (E), and MSImut and MSSmut (F). Abbreviations: MSI, microsatellite instability; MSImut, microsatellite instability and BRAF mutation; MSIwt, microsatellite instability and BRAF wild type; MSSmut, microsatellite stable and BRAF mutation; MSSwt, microsatellite stable and BRAF wild type; OS, overall survival.
Figure 7
Figure 7
Sensitivity analyses for publication bias analysis for associations of MSI/BRAF mutation status with OS in colorectal cancer. Notes: The colorectal cancer was divided into four subtypes according to the combination of MSI and BRAF mutation, ie, MSSwt, MSSmut, MSIwt, and MSImut. Sensitivity analyses were performed for OS comparison between MSSmut and MSSwt (A), MSIwt and MSSwt (B), MSImut and MSSwt (C), MSImut and MSIwt (D), MSIwt and MSSmut (E), and MSImut and MSSmut (F). Abbreviations: MSI, microsatellite instability; MSImut, microsatellite instability and BRAF mutation; MSIwt, microsatellite instability and BRAF wild type; MSSmut, microsatellite stable and BRAF mutation; MSSwt, microsatellite stable and BRAF wild type; OS, overall survival.
Figure 8
Figure 8
CRC stratification and prognosis comparison according to MSI and BRAF mutation status. Note: (A) Overall, (B) Stage I–III CRC, and (C) Stage IV CRC. Abbreviations: CRC, colorectal cancer; MSI, microsatellite instability; MSI/BRAFmut, microsatellite instability and BRAF mutation; MSI/BRAFwt, microsatellite instability and BRAF wild type; MSS/BRAFmut, microsatellite stable and BRAF mutation; MSS/BRAFwt, microsatellite stable and BRAF wild type.
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