| Abstract|| |
Background/Aims: The clinical relevance of the BRAF mutation in colorectal carcinoma (CRC) remains controversial. We performed a comprehensive meta-analysis to evaluate the precise relationship of BRAF mutation to clinicopathological features.
Materials and Methods: A systematic search of the electronic databases, including PubMed, the Web of Knowledge, and the China Journal Net was performed between January 2005 and December 2015. Outcomes of interest included gender, tumor site, tumor differentiation, node involvement, tumor size, and AJCC stage. We calculated the pooled odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for each study using a random or fixed-effect model.
Results: Twenty-five studies with a total of 13208 patients were included. BRAF mutation-positive CRC patients were 1464 (11.1%). Our meta-analysis revealed that, in patients with CRC, the BRAF mutation was associated with female, proximal site, poor differentiation, >5 cm size, and advanced AJCC stage.
Conclusions: This meta-analysis demonstrated that BRAF mutation was closely related to adverse pathological features and poor outcome of CRC.
Keywords: BRAF mutation, clinicopathological outcomes, colorectal cancer, meta-analysis
|How to cite this article:|
Li Y, Li W. BRAF mutation is associated with poor clinicopathological outcomes in colorectal cancer: A meta-analysis. Saudi J Gastroenterol 2017;23:144-9
|How to cite this URL:|
Li Y, Li W. BRAF mutation is associated with poor clinicopathological outcomes in colorectal cancer: A meta-analysis. Saudi J Gastroenterol [serial online] 2017 [cited 2018 Jun 22];23:144-9. Available from: http://www.saudijgastro.com/text.asp?2017/23/3/144/207712
| Introduction|| |
Colorectal carcinoma (CRC) is one of the most common malignancies and frequently takes a fatal course to human health worldwide. The development of CRC is a multistep process which included chromosomal abnormalities, gene mutations, and epigenetic modifications.,
BRAF and KRAS are both members of the Ras/Raf/MEK/MAP kinase cascade, which transduces various growth signals from the cell surface to the nucleus. Mutations of the genes encoding the KRAS and BRAF have been implicated in colorectal carcinogenesis. However, KRAS and BRAF mutations appear to be mutually exclusive.,
BRAF mutations occurred in 5–11% of CRC cases, and BRAF-mutant CRC has been associated with clinicopathological features,, including sex, tumor location, differentiation, lymph node involvement, and clinical stage. Some previous reports indicated that CRCs with BRAF mutations tend to be at a lower clinical stage,, whereas other studies ,, revealed CRCs with altered BRAF apt to have a poor prognosis. Therefore, it is necessary to use BRAF to make standard clinical and pathological staging more accurately for more effective clinical management. Thus, we conducted this meta-analysis to assess the correlation between the BRAF mutation and clinicopathological characteristics of the CRC.
| Materials and Methods|| |
A comprehensive literature review was performed from January, 2005 to December, 2015, using PubMed, Web of Knowledge, and the China Journal net. The search terms used were “BRAF,” “colon,” “rectal,” “rectum,” “tumor,” “cancer,” “neoplasm,” and “malignant.” The reference lists of relevant studies were checked manually to locate any missing studies.
Inclusion and exclusion criteria
Criteria for eligibility of a study included in this meta-analysis were (1) Detection of the BRAF mutation in the CRC tissues; (2) the studies published in English and Chinese; (3) when several studies were reported from the same authors or organizations, the meta-analysis enrolling the most recent or highest quality study only if the most recent one did not fit the inclusion criteria. Studies were excluded if (1) Studies were case reports, letters, and reviews without original data; animal or laboratory studies; (2) studies without clinicopathologic data were excluded; (3) repeated studies based on the same database or patients.
Two review authors (L.Y. and L.W.) independently selected studies for inclusion and extracted the data. A third researcher (Z.X.) arbitrated in the event of any disagreement. The decision for inclusion in the analysis was made by consensus. Full-text copies of potentially relevant studies were obtained. The following variables were recorded: authors, sex, number of patients, age of patients, histological cancer type, clinicopathological characteristics, and BRAF mutation rate.
A formal meta-analysis was done for all studies. The statistical analysis was carried out using the Review Manager 5.0. Pooled estimates of the complications were calculated using a fixed-effects model, but a random-effects model was used according to heterogeneity. The test of effect homogeneity was performed using χ2 tests, with P≤ 0.05 indicating significant heterogeneity. When the hypothesis of homogeneity was not rejected, the fixed-effects model was used to estimate the pooled effect of the outcomes; when the reverse was true, the random-effects model was also calculated. For the pooled analysis of the correlation between BRAF mutation and clinicopathological features (sex, tumor location, differentiation, lymph node involvement, and clinical stage), odds ratios (ORs), and 95% CI were combined to estimate the effect.
| Results|| |
We identified 2292 potentially relevant articles [Figure 1]. After exclusion of duplicate references, nonrelevant literature, and those manuscripts that did not satisfy the inclusion criteria, 76 articles were considered for the meta-analysis. After careful review of the full texts of these articles, 25 studies were included. The study characteristics are summarized in [Table 1].
After this review, 25 studies met the inclusion/exclusion criteria. A meta-analysis was performed of the 25 studies that evaluated 13208 patients. BRAF mutation-positive CRC patients were 1464, giving an overall frequency of 11.1%. The patient demographics for the 25 studies are presented in [Table 1]. All papers were retrospective chart reviews. The publication dates ranged from 2005 to 2015. The study sizes ranged from 43 to 2166 patients.
Twenty-four studies including 13043 patients demonstrated that there was a significant association between BRAF mutation and female gender (OR = 1.87; 95% CI = 1.66–2.09) [Figure 2]. Except this above mentioned parameter, controversies also existed on the correlation among tumor location, differentiation, lymph node metastasis, tumor size, AJCC stage, and BRAF mutation in these included studies. Eleven studies including 5307 patients were analyzed for the association between BRAF mutation and the location of the colorectal tumor. There was a significant association between BRAFV600E mutation and proximal colon tumor location (OR = 5.87; 95% CI = 3.72–9.24) [Figure 3]a. Twelve studies including 3569 patients were analyzed for the association between BRAF mutation and colorectal differentiation. There was a significant association between BRAF mutation and poor differentiation (OR = 3.57; 95% CI = 2.82–4.53) [Figure 3]b. In addition, two studies including 399 patients and 9 studies including 4154 patients reported the association between BRAF mutation and tumor size or AJCC stage. There was a significant correlation between the BRAF mutation and tumor size (OR = 2.63; 95% CI = 1.08–6.39) [Figure 3]d, advanced AJCC stage [OR = 1.63; 95% CI = 1.26–2.13) [Figure 3]e. However, for the cases of lymph node metastasis, 4 studies including 1142 patients were analyzed. The meta-analysis suggested that BRAF mutation was not correlated with lymph node metastasis (OR = 0.74; 95% CI = 0.47–1.17) [Figure 3]c.
|Figure 2: The association of BRAF mutation with demographics. Fixed effects model of the odds ratios (ORs) with 95% confidence intervals (CIs) for the association of BRAF mutation with gender|
Click here to view
|Figure 3: Random effects model of the odds ratios (ORs) with 95% confidence intervals (CIs) of the association of BRAF mutation with tumor site; (b) fixed effects model of the odds ratios (ORs) with 95% confidence intervals (CIs) of the association of BRAF mutation with tumor differentiation; (c) fixed effects model of the odds ratios (ORs) with 95% confidence intervals (CIs) of the association of BRAF mutation with node involvement; (d) fixed effects model of the odds ratios (ORs) with 95% confidence intervals (CIs) of the association of BRAF mutation with tumor size; (e) fixed effects model of the odds ratios (ORs) with 95% confidence intervals (CIs) of the association of BRAF mutation with AJCC stage|
Click here to view
| Discussion|| |
In our study, we confirmed that BRAF mutation was significantly associated with the high-risk clinicopathological factors of CRC and poor clinical outcome. To evaluate the relationship between BRAF mutation status and adverse clinicopathological outcomes, we performed a meta-analysis of 25 studies that evaluated 13208 patients. In our study, CRC patients with BRAF mutation exhibited 5.8 fold increase in female gender, poor differentiation, higher AJCC stages, proximal site, and size >5 cm comapared with patients with the wild-type form of the BRAF gene.
The BRAF V600E mutation has been validated independently as prognostic for overall survival and variable results have been obtained related to this mutation's association with traditional risk factors for higher mortality rate of CRC patients., Recently, significant correlations were found between BRAF mutation and the presence of right-sided tumors, poor differentiation, and mucinous histology.,,,,, Our meta-analysis provides new insights into the clinicopathological importance of the BRAF mutation in CRC and includes studies published after 2005.
Cantwell-Dorris reported the BRAF mutation of CRC with lymphatic metastasis as 5 to 10 times higher than that of CRC with lymph node negative. Compared to our study, the BRAF mutation did not show statistically significant association with lymph node metastasis. This might be explained by the limited studies included in our research.
Several mechanisms are involved in the aggressive phenotype of CRC that is promoted by the BRAF mutation. Ikenoue et al. indicated that the BRAF mutations of CRC can promote the activation of ERK, which activates downstream transcription factors to induce a range of biochemical processes including cell differentiation, proliferation, growth, while acting as the inhibitor of apoptosis.BRAF mutation of CRC also display deficiency in mismatch repair (MMR). The prevalence of BRAF mutation in MMR-deficient tumors has been shown to be three-fold greater than in MMR-proficient tumors.
There are several limitations of our meta-analysis. First, we did not evaluate the methods used to detect BRAF mutations for lacking data, which may affect the results. Second, we did not collect data on the treatment and clinical outcomes to analyze effect of the BRAF mutation on the overall clinical outcome. In addition, selection bias is also the domain that could lead to a biased estimate of the procedural effects in this analysis.
| Conclusions|| |
This meta-analysis demonstrated that BRAF mutation was closely related to adverse pathological features and poor outcome of CRC. BRAF mutation should be considered as a poor prognostic marker in CRC, and BRAF mutational analysis could result in better management for individual CRC patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007 CA. CA Cancer J Clin 2007;57:43-66.
Russo A, Rizzo S, Bronte G, Silvestris N, Colucci G, Gebbia N, et al
. The long and winding road to useful predictive factors for anti-EGFR therapy in metastatic colorectal carcinoma: The KRAS/BRAF pathway. Oncology 2009;77(Suppl 1):57-68.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al
. Genetic alterations during colorectal tumor development. Engl J Med 1998;319:525-32.
Jones S, Chen WD, Parmigiani G, Diehl F, Beerenwinkel N, Antal T, et al
. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A 2008;105:4283-8.
Rako I, Jakic-Razumovic J, Katalinic D, Sertic J, Plestina S. Mutation pattern of KRAS and BRAF oncogenes in colorectal cancer patients. Neoplasma 2012;59:376-83.
Yaeger R, Cercek A, Chou JF, Sylvester BE, Kemeny NE, Hechtman JF, et al
. BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancer. Cancer 2014;120:2316-24.
Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J, et al
. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30:2956-62.
Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al
. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006;38:787-93.
Zlobec I, Bihl MP, Schwarb H, Terracciano L, Lugli A. Clinicopathological and protein characterization of BRAF- and K-RAS-mutated colorectal cancer and implications for prognosis. Int J Cancer 2010;127:367-80.
Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, et al
. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 2002;62:6451-5.
Kadiyska TK, Konstantinova DV, Atanasov VR, Kremensky IM, Mitev VI. Frequency and application of the hot spot BRAF gene mutation (p.V600E) in the diagnostic strategy for Hereditary Nonpolyposis Colorectal Cancer. Cancer Detect Prev 2007;31:254-6.
Sclafani F, Gullo G, Sheahan K, Crown J. BRAF mutations in melanoma and colorectal cancer: A single oncogenic mutation with different tumour phenotypes and clinical implications. Crit Rev Oncol Hematol 2013;87:55-68.
Xu Q, Xu AT, Zhu MM, Tong JL, Xu XT, Ran ZH. Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: A meta-analysis. J Dig Dis 2013;14:409-16.
Pai RK, Jayachandran P, Koong AC, Chang DT, Kwok S, Ma L, et al
. BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: An aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol 2012;36:744-52.
Phipps AI, Buchanan DD, Makar KW, Burnett-Hartman AN, Coghill AE, Passarelli MN, et al
. BRAF mutation status and survival after colorectal cancer diagnosis according to patient and tumor characteristics. Cancer Epidemiol Biomarkers Prev 2012;21:1792-8.
Ang PW, Li WQ, Soong R, Iacopetta B. BRAF mutation is associated with the CpG island methylator phenotype in colorectal cancer from young patients. Cancer Lett 2009;273:221-4.
Bagadi SB1, Sanghvi M, Nair SB, Das BR. Combined mutational analysis of KRAS, NRAS and BRAF genes in Indian patients with colorectal carcinoma. Int J Biol Markers 2012;27:27-33.
Bozzao C, Varvara D, Piglionica M, Bagnulo R, Forte G, Patruno M, et al
. Survey of KRAS, BRAF and PIK3CA mutational status in 209 consecutive Italian colorectal cancer patients. Int J Biol Markers 2012;27:e366-74.
English DR, Young JP, Simpson JA, Jenkins MA, Southey MC, Walsh MD, et al
. Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG island methylator phenotype. Cancer Epidemiol Biomarkers Prev 2008;17:1774-80.
Fariña-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ, et al
. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol 2010;21:2396-402.
Gao J, Sun ZW, Li YY, Shen L. Mutations of KRAS and BRAF in Chinese patients with colorectal carcinoma: Analyses of 966 cases. Zhonghua Bing Li Xue Za Zhi 2012;41:579-83.
Ikehara N, Semba S, Sakashita M, Aoyama N, Kasuga M, Yokozaki H. BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms. Int J Cancer 2005;115:943-50.
Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH. Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int 2008;58:104-13.
Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B. BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status. Mol Cancer 2006;5:2.
Martinetti D, Costanzo R, Kadare S, Alimehmeti M, Colarossi C, Canzonieri V, et al
. KRAS and BRAF mutational status in colon cancer from Albanian patients. Diagn Pathol 2014;9:187.
Phipps AI, Buchanan DD, Makar KW, Burnett-Hartman AN, Coghill AE, Passarelli MN, et al
. BRAF mutation status and survival after colorectal cancer diagnosis according to patient and tumor characteristics. Cancer Epidemiol Biomarkers Prev 2012;21:1792-8
Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al
. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 2010;28:466-74.
Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, et al
. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 2005;65:6063-9.
Shaukat A, Arain M, Thaygarajan B, Bond JH, Sawhney M. Is BRAF mutation associated with interval colorectal cancers? Dig Dis Sci 2010;55:2352-6.
Tie J, Gibbs P, Lipton L, Christie M, Jorissen RN, Burgess AW, et al
. Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer 2011;128:2075-84.
Ye JX, Liu Y, Qin Y, Zhong HH, Yi WN, Shi XY. KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients. World J Gastroenterol 2015;21:1595-605.
Yokota T, Ura T, Shibata N, Shitara K, Nomura M, Kondo C, et al
. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer 2011;104:856-62.
Yoshitake N, Fujii S, Mukawa K, Tominaga K, Fukui H, Ichikawa K, et al
. Mutational analysis of the BRAF gene in colorectal mucinous carcinoma in association with histological configuration. Oncol Rep 2007;17:9-15.
Deng G, Kakar S, Tanaka H, Matsuzaki K, Miura S, Sleisenger MH, et al
. Proximal and distal colorectal cancers show distinct gene-specific methylation profiles and clinical and molecular characteristics. Eur J Cancer 2008;44:1290-301.
Kalady MF, Sanchez JA, Manilich E, Hammel J, Casey G, Church JM. Divergent oncogenic changes influence survival differences between colon and rectal adenocarcinomas. Dis Colon Rectum 2009;52:1039-45.
Cantwell-Dorris ER, O'Leary JJ, Sheils OM. BRAFV600E: Implications for carcinogenesis and molecular therapy. Mol Cancer Ther 2011;10:385-94.
Ikenoue T, Hikiba Y, Kanai F, Aragaki J, Tanaka Y, Imamura J, et al
. Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor kappaB pathway and cellular transformation. Cancer Res 2004;64:3428-35.
Erhardt P, Schremser EJ, Cooper GM. B-Raf inhibit programmed cell death downstream of cytochrome c release from mitochondria by activating the MEK/Erk pathway. Mol Cell Biol 1999;19:5308-15.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002;418:934.
Department of Colorectal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]