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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 7  |  Page : 191-198

Evaluation and identification of factors related to KRAS and BRAF gene mutations in colorectal cancer: A meta-analysis


1 Department of Gastrointestinal Oncology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, People's Republic of China
2 Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
3 Department of Pathology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, People's Republic of China
4 Department of Integrated Chinese Traditional Medicine and Western Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People's Republic of China

Date of Web Publication21-Feb-2017

Correspondence Address:
Mei-yu Fang
Department of Integrated Chinese Traditional Medicine and Western Medicine, Zhejiang Cancer Hospital, No. 38 Guangji Road, Gongshu District, Hangzhou, Zhejiang 310022
People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.200601

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 > Abstract 

Objective: The aim of this meta-analysis is to evaluate the distribution pattern of KRAS and BRAF mutations in colorectal cancer.
Materials and Methods: The database was searched without language restrictions. Meta-analyses were conducted using the STATA software. We calculated the odds ratio (OR) and its 95% confidence interval (95% CI) to estimate the distribution of and correlation between KRAS and BRAF mutations, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) in left- and right-sided colorectal cancer.
Results: The studies were divided into five groups: (1) distribution of KRAS/BRAF mutations in distal and proximal colorectal cancer, the summary OR value was 1.24 versus 4.03, (2) distribution of KRAS/BRAF mutations in CIMP-low/Neg and CIMP-high (CIMP-H) tumors, the summary OR value was 0.77 versus 10.49, (3) distribution of KRAS/BRAF mutations in MSI-low (MSI-L)/microsatellite stable (MSS) and MSI-high (MSI-H) tumors, the summary OR value was 0.51 versus 9.60, (4) proportion of CIMP-H/MSI-H tumors among distal and proximal colorectal tumors, the summary OR value was 3.66 versus 6.54, and (5) proportion of CIMP-H tumors among MSI-L/MSS and MSI-H tumors, the summary OR value was 5.87.
Conclusion: The meta-analysis reveals that KRAS has a slightly higher mutation rate in MSI-L/MSS tumors. Moreover, BRAF mutations have higher detection rates in right-sided colorectal cancer, which suggests that BRAF mutations are likely in CIMP-H tumors. Therefore, based on these findings, the molecular diagnostic tests to be conducted in colorectal cancer patients can be determined according to the location/clinical features of the tumor.

Keywords: BRAF gene, colorectal, CpG island methylator phenotype, KRAS gene, microsatellite instability, mutation, tumor


How to cite this article:
Lin L, Chen Gy, Xu Cw, Wang Hy, Wu Yf, Fang My. Evaluation and identification of factors related to KRAS and BRAF gene mutations in colorectal cancer: A meta-analysis. J Can Res Ther 2016;12, Suppl S3:191-8

How to cite this URL:
Lin L, Chen Gy, Xu Cw, Wang Hy, Wu Yf, Fang My. Evaluation and identification of factors related to KRAS and BRAF gene mutations in colorectal cancer: A meta-analysis. J Can Res Ther [serial online] 2016 [cited 2019 Jul 19];12:191-8. Available from: http://www.cancerjournal.net/text.asp?2016/12/7/191/200601


 > Introduction Top


Currently, the use of epidermal growth factor receptor-targeted drugs in the treatment of colorectal cancer is determined based on the mutation status of the KRAS and BRAF genes; therefore, tests for detecting mutations in these genes are performed before the targeted therapy for colorectal cancer is decided.[1] The detection rate of KRAS and BRAF mutations has been reported to be 50% and 10%, respectively, in patients with colorectal cancer.[2] The mutation rates of genes are associated with the methylation of various DNA mismatch repair genes; the proportion of which determines the CpG island methylator phenotype (CIMP).[3] Due to the high correlation between microsatellite instability (MSI) and CIMP, MSI can to some extent reflect CIMP [4] and be used as an indicator of the rate of KRAS and BRAF gene mutations. There is a considerable difference in the incidence of methylation of DNA mismatch repair genes among tumors in different regions of the colon and rectum, which results in differences in the distribution of tumors with mutated KRAS and BRAF genes in the colon and rectum.

This paper investigates the distribution patterns of KRAS and BRAF mutations and their relation to the MSI and CIMP status.


 > Materials and Methods Top


Study selection

To identify relevant studies, we searched several databases, including PubMed, Web of Science, EMBASE, and the Cochrane Library, using the keywords “CRC” or “Colorectal Cancer,” “KRAS,” “BRAF,” and “Methylation,” for articles published up to September 30, 2014. The following inclusion criteria were applied: (1) the tumor tissue samples were obtained from patients definitely diagnosed with colorectal cancer; (2) the sample size was not <50, and the tumor locations were known; (3) two or more indices, from KRAS mutations, BRAF mutations, CIMP, and MSI were assessed; (4) correlation analysis was performed based on the above indices. We excluded (1) studies on nonprimary tumors, (2) studies on animal models, (3) studies in which related genes or genotypes were not analyzed at all, and (4) papers that were not research articles, including reviews.

Statistical analysis

STATA 12.1 (Stata Corp, College Station, TX) was used for all the statistical analyses. The P value and heterogeneity index I2 were determined using heterogeneity tests. P ≥ 0.10 was considered to indicate homogeneity, while P < 0.10 was considered to indicate heterogeneity. I2 values higher than 25%, 50%, and 75% were considered to be indicative of low, intermediate, and high heterogeneity, respectively. The model for each data group was adopted based on the results of the heterogeneity test. The fixed-effects model was adopted for homogeneous data groups, while the random-effects model was adopted for heterogeneous data groups. The weighted sum of each result in a group was determined to calculate the summary odds ratios (ORs) and their corresponding 95% confidence intervals (CI). The summary ORs were compared using the Z test, and the summary ORs were considered significant when the corresponding P < 0.05.


 > Results Top


Selection and characteristics of the included studies

Sixty-four full articles were obtained from the initial search; four of which were excluded because the papers were identical. After browsing through the full articles or abstracts, we further excluded 28 out of the 60 papers based on our exclusion criteria mentioned in the previous section. The remaining 32 articles were primary articles. After reading the 32 primary articles, we excluded 8 of them because of problems with the data or statistics.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] Therefore, a total of 24 papers were finally included in our analysis [Figure 1].
Figure 1: Flowchart of study selection

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The 24 included articles were published between 2004 and 2012 and they were all comparative studies. The age range of the study participants was between 13 and 92 years, and the participants were mainly distributed in East Asian, Western and Northern Europe, Australia, and North America, specifically, from China, Hong Kong, Korea, Japan, France, Germany, The Netherlands, Sweden, Czech, Australia, and the United States of America. In most of the studies, the median or average age of the subjects ranged between 60 and 70 years (studies without age-related information were not included). The total number of participants was 7096, and there were more male than female participants. Adenocarcinoma was the most common histopathological tumor type. The methods used for assessing KRAS and BRAF mutations, CIMP, and MSI/microsatellite stable (MSS) are listed in [Table 1].
Table 1: Characteristics of the included studies

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Quantitative synthesis

The studies were divided into five groups, with a total of nine subgroups: (1) distribution of KRAS/BRAF mutations in distal and proximal colorectal cancer, (2) distribution of KRAS/BRAF mutations in CIMP-low (CIMP-L)/Neg and CIMP-high (CIMP-H tumors), (3) distribution of KRAS/BRAF mutations in MSI-low (MSI-L)/MSS and MSI-high (MSI-H) tumors, (4) proportion of CIMP-H/MSI-H tumors among distal and proximal colorectal tumors, and (5) proportion of CIMP-H tumors among MSI-L/MSS and MSI-H tumors. Within each group, the combined effect of multiple studies was directly observed using forest plots, while the combined bias was evaluated using funnel plots. The results of the meta-analysis for each group are shown below.

Distribution of KRAS mutations in distal and proximal colorectal cancer

A total of ten studies were included in this subgroup. The total sample sizes for distal and proximal colorectal cancer were 1031 and 703, respectively, while the total sizes for distal and proximal cancer with KRAS mutations were 533 and 283, respectively. Significant homogeneity was found between the studies in this group (P = 0.208, I2 = 25.6%), and the fixed-effects model was, therefore, adopted. Seven out of ten studies had an OR value higher than 1, and the OR value was not statistically significant for any of the studies in this subgroup. The summary OR value was 1.24 (Z = 2.50, P = 0.012), and the CI of the summary OR did not intersect the invalid line. This result suggests that KRAS mutations are likely to have significantly higher detection rates in proximal colorectal cancer than in distal colorectal cancer. However, for all the 24 studies in total, the CI intersected with the invalid line; hence, it seems that the results of all the studies together are not in agreement with those of this group [Figure 2]a.
Figure 2: Forest plots: (a) Distribution of KRAS mutations in distal and proximal colorectal tumors. (b) Distribution of BRAF mutations in distal and proximal colorectal tumors. (c) Distribution of KRAS mutations in CpG island methylator phenotype-low/negative and CpG island methylator phenotype-high tumors. (d) Distribution of BRAF mutations in CpG island methylator phenotype-low/negative and CpG island methylator phenotype-high tumors. (e) Distribution of KRAS mutations in microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors. (f) Distribution of BRAF mutations in microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors. (g) Distribution of CpG island methylator phenotype-high tumors among distal and proximal colorectal tumors. (h) Distribution of microsatellite instability-high tumors among distal and proximal colorectal tumors. (i) Distribution of CpG island methylator phenotype-high tumors among microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors

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Distribution of BRAF mutations in distal and proximal colorectal cancer

A total of 15 studies were included in this subgroup. The total sample sizes for distal and proximal colorectal cancer were 1716 and 938, respectively, while the total sample sizes for distal and proximal colorectal cancer, in which BRAF mutations were detected, were 65 and 190, respectively. There was significant homogeneity between the studies (P = 0.091, I2 = 34.7%), and the fixed-effects model was, therefore, adopted. All the studies had an OR value higher than 1, and the OR values were statistically significant for eight studies. The summary OR value was 4.03 (Z = 8.84, P = 0.000), which suggests that BRAF mutations have a significantly higher detection rate in proximal colorectal cancer than in distal colorectal cancer [Figure 2]b.

Distribution of KRAS mutations in CpG island methylator phenotype-low/negative and CpG island methylator phenotype-high tumors

A total of eight studies were included in this subgroup. The total sample sizes for the CIMP-L/Neg and CIMP-H tumors were 1354 and 384, respectively, while the total sample sizes for CIMP-L/Neg and CIMP-H tumors, in which KRAS mutations were detected, were 507 and 113, respectively. There was significant homogeneity between these studies (P = 0.499, I2 = 0%), and the fixed-effects model was, therefore, adopted. Three of the eight studies had an OR value >1, and the OR value was statistically significant only for one study of this subgroup. The summary OR value was 0.77 (Z = 2.13, P = 0.033), which suggests that KRAS mutations have slightly higher detection rates in CIMP-L/Neg tumors than in CIMP-H tumors. However, the opposite conclusion was derived from one study, with statistical significance [Figure 2]c.

Distribution of BRAF mutations in CpG island methylator phenotype-low/negative and CpG island methylator phenotype-high tumors

A total of 12 studies were included in this subgroup. The total sample sizes for CIMP-L/Neg and CIMP-H tumors were 2057 and 530, respectively, while the total sample sizes for CIMP-L/Neg and CIMP-H tumors with BRAF mutations were 123 and 237, respectively. There was significant heterogeneity between these studies (P = 0.000, I2 = 71.8%), so the random-effects model was adopted. All the studies had an OR value higher than 1, and the OR value was statistically significant for 11 studies in this subgroup. The summary OR value was 10.49 (Z = 7.81, P = 0.000), which suggests that BRAF mutations have significantly higher detection rates in CIMP-H colorectal tumors than in CIMP-L/Neg colorectal tumors [Figure 2]d.

Distribution of KRAS mutations in microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors

A total of seven studies were included in this subgroup. The total sample sizes for MSI-L/MSS and MSI-H tumors were 1626 and 227, respectively, while the total sample sizes for MSI-L/MSS and MSI-H tumors with KRAS mutations were 627 and 45, respectively. There was significant homogeneity between these studies (P = 0.540, I2 = 0%), so the fixed-effects model was adopted. All the studies had an OR value higher than 1, and the OR value was statistically significant for only one study. The summary OR value was 0.51 (Z = 3.81, P = 0.000), which suggests that KRAS mutations have significantly higher detection rates in MSI-L/MSS colorectal tumors than in MSI-H colorectal tumors [Figure 2]e.

Distribution of BRAF mutations in microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors

A total of ten studies were included in this subgroup. The total sample sizes of MSI-L/MSS and MSI-H tumors were 2512 and 338, respectively, while the total sample sizes of MSI-L/MSS and MSI-H tumors with BRAF gene mutations were 124 and 182, respectively. There was significant homogeneity between these studies (P = 0.757, I2 = 0%), and the fixed-effects model was, therefore, adopted. All the studies had an OR value higher than 1, and therefore, the OR value was statistically significant for this entire subgroup. The summary OR value was 9.60 (Z = 16.24, P = 0.000), which suggests that BRAF mutations have significantly higher detection rates in MSI-H colorectal tumors than in MSI-L/MSS colorectal tumors [Figure 2]f.

Proportion of CpG island methylator phenotype-high tumors among distal and proximal colorectal tumors

A total of eight studies were included in this subgroup. The total sample sizes of distal and proximal colorectal cancer were 1336 and 766, respectively, while the total sample sizes of CIMP-H distal and proximal colorectal cancer were 150 and 276, respectively. There was significant heterogeneity between these studies (P = 0.000, I2 = 74.4%), so the random-effects model was adopted. All the studies had an OR value higher than 1, and the ORs for six studies were statistically significant. The summary OR value was 3.66 (Z = 4.95, P = 0.000), which suggests that the proportion of CIMP-H tumors is significantly higher among distal colorectal tumors than proximal colorectal tumors [Figure 2]g.

Proportion of microsatellite instability-high tumors among distal and proximal colorectal tumors

A total of six studies were included in this subgroup. The total sample sizes of distal and proximal colorectal cancer were 1370 and 648, respectively, while the total sample sizes of MSI-H distal and colorectal cancer were 49 and 159, respectively. There was significant homogeneity between these studies (P = 0.631, I2 = 0%), and the fixed-effects model was, therefore, adopted. All studies had an OR value higher than 1, and the ORs for all the studies were statistically significant. The summary OR value was 6.54 (Z = 10.87, P = 0.000), which suggests that the proportion of MSI-H tumors is significantly higher among proximal colorectal tumors than distal colorectal tumors [Figure 2]h.

Proportion of CpG island methylator phenotype-high tumors among microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors

A total of nine studies were included in this subgroup. The total sample sizes of MSI-L/MSS and MSI-H tumors were 1430 and 277, respectively, while the total sample sizes of CIMP-H MSI-L/MSS and MSI-H tumors were 136 and 165, respectively. There was significant heterogeneity between these studies (P = 0.014, I2 = 58.1%), and the random-effects model was, therefore, adopted. All the studies had an OR value higher than 1, and the OR values for seven studies were statistically significant. The summary OR value was 5.87 (Z = 7.73, P = 0.000), which suggests that the proportion of CIMP-H tumors is significantly higher among MSI-H colorectal tumors than MSI-L/MSS colorectal tumors [Figure 2]i.

Publication bias

Funnel plots are commonly used for direct evaluation of biases in summary data; the logarithmic values of OR are plotted on the horizontal axes, and the standard deviations of log OR are plotted on the vertical axes. The vertical solid lines represent the summary ORs, and the slashes (dashed lines) on both sides represent the 95% CIs of the summary ORs. The publication bias for each subgroup is analyzed below based on the symmetry of the funnel plots. For Subgroup 1A (distribution of KRAS mutations in distal and proximal colorectal tumors), the funnel plots are symmetrical, and there is, therefore, no publication bias. For Subgroup 1B (distribution of BRAF mutations in distal and proximal colorectal tumors), the funnel plots are asymmetrical at the bottom, and the studies are far off from the central axis, which indicates a publication bias. For Subgroup 2A (distribution of KRAS mutations in CIMP-L/Neg and CIMP-H tumors), the funnel plots are basically symmetrical, and there is, therefore, no publication bias. For Subgroup 2B (distribution of BRAF mutations in CIMP-L/Neg and CIMP-H tumors), the funnel plots are asymmetrical, which indicates a publication bias. For Subgroup 3A (distribution of KRAS mutations in MSI-L/MSS and MSI-H tumors), the funnel plots are basically symmetrical, and there is, therefore, no publication bias. For Subgroup 3B (distribution of BRAF mutations in MSI-L/MSS and MSI-H tumors), the funnel plots are symmetrical, and there is, therefore no publication bias. For Subgroup 4A (proportion of CIMP-H tumors among distal and proximal colorectal tumors), the funnel plots are asymmetrical, and there is, therefore, a publication bias. For Subgroup 4B (proportion of MSI-H tumors among distal and proximal colorectal tumors), the funnel plots are asymmetrical, which indicates a publication bias. For subgroup 5 (proportion of CIMP-H tumors among MSI-L/MSS and MSI-H tumors), the funnel plots are basically symmetrical, and there is, therefore, no publication bias [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d,[Figure 3]e,[Figure 3]f,[Figure 3]g,[Figure 3]h,[Figure 3]i.
Figure 3: Funnel plots: (a) Distribution of KRAS mutations in distal and proximal colorectal tumors: Funnel plots are symmetrical, so there is no publication bias. (b) Distribution of BRAF mutations in distal and proximal colorectal tumors: Funnel plots are asymmetrical at the bottom, and the included studies are far off the central axis, which indicates a publication bias. (c) Distribution of KRAS mutations in CpG island methylator phenotype-low/negative and CpG island methylator phenotype-high tumors: Funnel plots are basically symmetrical, so there is no publication bias. (d) Distribution of BRAF mutations in CpG island methylator phenotype-low/negative and CpG island methylator phenotype-high tumors: Funnel plots are asymmetrical, which indicates a publication bias. (e) Distribution of KRAS mutations in microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors: Funnel plots are basically symmetrical, so there is no publication bias. (f) Distribution of BRAF mutations in microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors: Funnel plots are symmetrical, so there is no publication bias. (g) Distribution of CpG island methylator phenotype-high tumors among distal and proximal colorectal tumors: Funnel plots are asymmetrical, which indicates a publication bias. (h) Distribution of microsatellite instability-high tumors among distal and proximal colorectal tumors: Funnel plots are asymmetrical, which indicates a publication bias. (i) Distribution of CpG island methylator phenotype-high tumors among microsatellite instability-low/microsatellite stable and microsatellite instability-high tumors: Funnel plots are basically symmetrical, so there is no publication bias

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 > Discussion Top


The meta-analysis conducted in this study revealed some important patterns about the incidence of KRAS and BRAF mutations in proximal and distal colorectal tumors and their CIMP and MSI status.

Based on the results of the meta-analysis of each group, the incidence rates of tumors in the distal colon and rectum (left side of the colon and rectum) were substantially higher than those of tumors in the proximal colon and rectum (right side of the colon and rectum). Further, the rate of KRAS mutations in the colorectal tumor samples showed no apparent distributive tendency with regard to tumor location (colon and rectum). In addition, meta-analyses of the CIMP and MSI status of tumors showed that the rates of KRAS mutations were higher in CIMP-L/Neg and/or MSI-L/MSS colorectal tumors, while the incidence rates of MSI-L/MSS tumors were higher in the distal colon and rectum. These results indicate that KRAS mutations have higher detection rates in the distal colon and rectum.

As shown in previous studies,[29],[30] patients diagnosed with MSI-H colorectal cancer had better survival than those diagnosed with MSI-L/MSS colorectal cancer. Based on the high mutation rates of the KRAS gene in the colorectal tumor samples and the results of the meta-analyses in this study, we think that KRAS mutations have higher detection rates in MSI-L/MSS colorectal tumors and that the incidence rates of CIMP-L/Neg tumors are higher in the distal colon and rectum.

According to the results of the meta-analyses, the incidence rates of KRAS mutations are higher in MSI-L/MSS colorectal tumors. Based on the high correlation of both MSI and gene mutations with the CIMP of DNA mismatch repair genes, the incidence rates of KRAS mutations should be theoretically higher in CIMP-L/Neg colorectal tumors. However, our meta-analyses demonstrated that the incidence rates of KRAS mutations are only slightly higher in CIMP-L/Neg colorectal tumors, and some studies have even shown that KRAS mutations have no correlation with the CIMP of DNA mismatch repair genes.[30] In our study, CIMP showed some association with KRAS mutations, but this is probably related to the complicated mechanisms underlying gene mutations in tumors.[31]

The meta-analyses revealed the apparent distribution pattern of BRAF mutations: the incidence rates of BRAF mutations, CIMP-H, and MSI-H are significantly higher in proximal colorectal tumors than in distal colorectal tumors, and BRAF mutations are highly correlated with CIMP-H and MSI-H. Therefore, we speculated that the detection rates of BRAF gene mutations, MSI-H, and CIMP-H are higher in proximal colorectal tumors and that the detection of abnormality in any one of these three indices can indicate abnormality in the other two indices.

The above conclusions can to some extent link the clinical analysis of colorectal tumors to the molecular diagnosis of samples. For example, if the primary tumor is known to be located in the right side of the colon, more consideration should be given to the detection of BRAF mutations and MSI. Moreover, if a tumor sample is confirmed as MSI-L/MSS in the molecular diagnosis, KRAS mutations and poor prognosis should be expected.


 > Conclusion Top


  1. KRAS mutations have no apparent distribution pattern in colorectal tumors at different locations
  2. However, based on the distribution of MSI-L/MSS and MSI-H colorectal tumors and their KRAS mutation rates, it is possible that KRAS mutations may be more frequent in distal colorectal tumors
  3. The incidence rates of BRAF mutations are higher in the proximal colon and rectum, and
  4. BRAF gene mutations are highly correlated with CIMP-H.


Financial support and sponsorship

This study is supported by the Medical Scientific Research Foundation of Zhejiang Province of China (Grant no. 2013 KYB051) and Zhejiang Administration of Traditional Chinese Medicine Foundation (Grant no. 2013ZQ005).

Conflict of interest

There are no conflicts of interest.

 
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