Abstract
Introduction: There have been contradictory data on whether or not BRAF V600E mutation should be regard as a poor prognosis predictor of papillary thyroid carcinoma (PTC). To settle down the conflict, this metaanalysis is prepared to clarify the present prognostic role of BRAF V600E mutation in patients with PTC. Methods and materials: The relevant published researches were incorporated according to the defined inclusion/exclusion criteria from PubMed. The effect sizes of outcome parameters were estimated by hazard ratios (HRs). Results: The current meta-analysis included 19 researches with a total of 6087 patients. We have found that patients with BRAF V600E mutation have a poor overall survival (the pooled HR=2.91, 95% confidence interval (CI): 1.35-6.29). Furthermore, subgroup analysis of the recurrence-free survival (RFS) of PTC patients by races indicated that BRAF V600E mutation predicts poor RFS of patients (the pooled HR=1.63, 95% CI: 1.37-1.93), both Caucasian (the pooled HR=1.57, 95% CI: 1.30-1.90) and Asian (the pooled HR=1.91, 95% CI: 1.28-2.87). Conclusions: The poor prognosis predicted role of BRAF V600E mutation in PTC was certified from the current meta-analysis. The BRAF V600E mutation may be used as a prognostic predictor of patients with PTC.
Keywords: Thyroid, thyroid papillary carcinoma (PTC), BRAF V600E mutation, meta-analysis
Introduction
As a common malignant tumor type of endocrine system, thyroid papillary carcinoma (PTC) including several subtypes such as common conventional PTC, follicular-variant PTC [1]. Compared to other types of malignancy, PTC is relatively a highly curable disease. PTC patients usually have high rate of overall 10-year survival (>90%), however, the main troubles of patients with PTC are regional recurrences and distant metastases [2]. To evaluate the prognosis of patients, several clinicopathologic factors were implemented, including age (>45 years old), gender (male), lymph nodes metastasis, extra-thyroidal extension, distant metastasis, aggressive histological subtype and advanced disease stages [3].
In addition, some biochemical markers (especially the BRAF V600E mutation) also been used to predict the cancer associated prognosis of PTC patients. As we known that, the BRAF V600E mutation is the most common mutation of PTC and associated with activation of the mitogen activated protein Kinase signaling pathway [4]. Numerous researches have revealed the BRAF V600E mutation statue in different subtypes of PTC, furthermore, estimated the correlation between the BRAF V600E mutation statue and various clinicopathologic factors of patients with PTC. And a recent study have pooled the reported data and conducted a meta-analysis to comprehensively evaluate the relationship between BRAF mutation and clinicopathological features of PTC [5]. Researchers [5] displayed that BRAF mutation is associated with male gender, LNM, stage, extra-thyroidal extension, tumor size, multifocality, classic PTC, and tall-cell variant PTC in PTC.
However, there is still conflicting about whether or not the BRAF V600E mutation could be a poor prognosis predictor of PTC patients. Some studies found that there have no significant relationship between the BRAF V600E mutation and PTC prognosis [6]. But other researches implied that the BRAF V600E mutation predicts poor overall survival (OS) and/or recurrence-free survival (RFS) of PTC patients [7]. For comprehensively understanding the role of the BRAF V600E mutation in PTC prognosis, it’s necessary for us to conduct a meta-analysis to quantitatively pool the reported data and completely explore the relationship between the BRAF V600E mutation and survival of PTC patients.
Methods and materials
Database and retrieval strategy
Because of its comprehensive coverage fraction of published researches, we used PubMed (http://www.ncbi.nlm.nih.gov/pubmed) as our target database for reference retrieval. The retrieval strategy involving the following keywords variably combined by “BRAF V600E mutation”, “thyroid”, “thyroid papillary carcinoma”, “carcinoma”, “survival outcomes” and “prognosis”.
Eligibility criteria
Inclusion criteria: (I) the target disease is thyroid papillary carcinoma; (II) the prognostic role of the BRAF V600E mutation was studied including overall survival (OS), progression free survival or disease free survival (PFS/DFS); (III) the latest or most informative single article was included when articles were derived from the same authors/groups. Exclusion criteria: (I) these article types are excluded: review, letter, laboratory research, or mechanism study; (II) the article is duplicated; (III) it lacked critical original data for meta-analysis.
Data extraction and Statistical analysis
The above references were screened according to the inclusion/exclusion criteria, by two authors. The reported data about the relationship between the BRAF V600E mutation and survival outcomes (OS, RFS and DFS) of PTC patients were extracted, the data types including reported survival data, the Kaplan-Meier (K-M) curves or HR and 95% CI. Also, the baseline characteristics of eligible articles were extracted by the other two researchers independently. The K-M curves’ data was extracted by Engauge Digitizer 4.1 (http://sourceforge.net). The multivariate cox hazard regression analysis data is first choice, if cannot obtained, univariate Cox hazard regression analysis or K-M survival curves of survival outcomes were instead, then reported survival data was the last choice for HR (95% CI) calculation.
STATA 11.0 (STATA Corporation, College Station, TX) was used to conduct the current meta-analysis. Heterogeneity was defined as P<0.05 or I2≥50%, a fixed effect model was used for pooled HRs calculation. On the contrary, if heterogeneity was fine (P≥0.05, I2<50%), a random effect model was used for pooled HRs calculation. If the pooled HR>1 and the 95% CI exclude 1, it indicated a significant worse outcome for the case group compared to the control group. The publication bias was tested by Begg’s test and Egger’s test, P<0.05 indicating that potential publication bias existed.
Results
Eligible articles filtration process
After total two steps of filtration, 19 articles [6-24] were recognized as finial eligible articles (Figure 1). At the first step, we initial included 305 references after retrieved the database of PubMed. Then 275 articles were excluded after reading the titles and abstracts. Among them, 68 articles were not associated with the prognostic role of the BRAF V600E mutation in PTC. 51 articles were review articles. 50 articles were excluded because they were focused on mechanism researches. 42 articles were excluded because they were not referred to the BRAF V600E mutation and/or PTC. 39 articles were just referred to diagnosis studies. 15 articles were case report articles, 5 articles were meta-analysis articles and the other 5 articles were not published in English. At the second step, 30 articles were included for comprehensive filtration, and 11 articles were further excluded because 5 articles were not associated with the prognostic role of the BRAF V600E mutation in PTC, 3 articles have no enough original data for meta-analysis and 3 articles were published by the same authors/groups. The baseline characteristics of eligible articles were listed in Table 1.
Table 1.
Ref. | Ethnic | Accounts | Follow up | Survival outcomes | Attitudes of BRAF mutation | Study type | Measurement of BRAF mutation |
---|---|---|---|---|---|---|---|
Niederer-Wüst SM et al. 2015 | Caucasian | 116 | 2-252 mon. | OS/RFS | Insignificance | Retrospective | PCR |
Daliri M et al. 2014 | Asian | 69 | 12-192 mon. | OS/RFS | Insignificance | Prospective | SSCP |
McKelvie PA et al. 2013 | Caucasian | 77 | 20-192 mon. | OS/RFS | Insignificance | Prospective | C-PCR |
Ito Y et al. 2014 | Asian | 766 | 13-191 mon. | OS/RFS | Insignificance | Retrospective | PCR |
Elisei R et al. 2012 | Caucasian | 319 | 5.3±0.8 yr. | DFS | Poor prognosis | Prospective | SSCP |
Pelttari H et al. 2012 | Caucasian | 51 | 16 yr. | RFS | Insignificance | Retrospective | Allelic specific PCR with Scorpions rt-PCR |
Guerra A et al. 2012 | Caucasian | 168 | 3-195 mon. | RFS | Insignificance | Retrospective | BigDye terminator sequencing and pyrosequencing |
Elisei R et al. 2008 | Caucasian | 102 | 15 yr. | OS/DFS | Poor prognosis | Retrospective | SSCP |
Kim TY et al. 2006 | Asian | 203 | 10 yr. | DFS | Poor prognosis | Retrospective | PCR amplification and direct sequencing |
Huang FJ et al. 2014 | Asian | 214 | 12-50 mon. | RFS | Poor prognosis | Prospective | Sanger sequencing |
Henke LE et al. 2015 | Caucasian | 508 | 8.0 yr. | OS/RFS | Insignificance | Retrospective | SSCP |
Prescott JD et al. 2012 | Caucasian | 205 | 5.0 yr. | RFS | Poor prognosis | Retrospective | SSCP |
Danilovic DL et al. 2014 | Caucasian | 178 | 33.5±7.2 mon. | RFS | Poor prognosis | Retrospective | Re-PCR genotyping technique |
He G et al. 2014 | Asian | 187 | 24 mon. | RFS | Poor prognosis | Retrospective | Allelic specific PCR |
Xing M et al. 2015 | Caucasian | 2099 | 13-67 mon. | RFS | Poor prognosis | Retrospective | BigDye terminator sequencing and pyrosequencing |
Xing M et al. 2005 | Caucasian | 219 | 14 yr. | RFS | Poor prognosis | Retrospective | BigDye terminator sequencing and pyrosequencing |
Kebebew E et al. 2007 | Caucasian | 314 | 72±33 mon. | RFS | Poor prognosis | Retrospective | BigDye terminator sequencing and pyrosequencing |
Russo M et al. 2014 | Caucasian | 103 | 56.9±14.1 mon. | RFS | Insignificance | Retrospective | PCR |
Pelizzo MR et al. 2014 | Caucasian | 189 | 1-156 mon. | RFS | Insignificance | Retrospective | SSCP |
Months, mon.; Overall survival, OS; Recurrence-free survival, RFS; Year, yr.; Disease-free survival, DFS; polymerase chain reaction, PCR; PCR-single-strand conformation polymorphism analysis.
OS
Six articles listed the relationship between the BRAF V600E mutation and OS of PTC patients. The heterogeneity have not been found (P=0.666, I2=0.0%), and a fixed effect model was used. We found that the pooled HR (95% CI) is 2.91 (1.35, 6.29) (Figure 2).
RFS
Only two articles have reported the DFS data, however the remaining articles are all reported the RFS data. For convenience of meta-analysis, we have combined DFS data and RFS data to calculate the pooled HR (95% CI). The heterogeneity test revealed that P=0.130 and I2=27.4%, therefore a fixed effect model was used. We found that the pooled HR (95% CI) is 1.63 (1.37, 1.93) (Figure 3). Furthermore, subgroup analysis indicated that BRAF V600E mutation predicts poor RFS of patients, both Caucasian (the pooled HR=1.57, 95% CI: 1.30-1.90) and Asian (the pooled HR=1.91, 95% CI: 1.28-2.87) (Figure 3).
Publication bias
We have not found any publication bias through Begg’s funnel plot (Figure 4) and Egger’s test. The P value of Egger’s test is 0.069. In addition, we have conducted sensitivity analysis both for RFS and OS, to exam their stability. And the results were displayed in Supplementary Figure 1. A is the result for OS, and B is for RFS. We cannot found instability of results from the sensitivity analysis.
Discussion
Even though various types of meta-analysis have been conducted to evaluate the relationships between the BRAF V600E mutation and clinicopathologic characteristics of PTC patients. There have no associated meta-analysis which was implemented to analysis the correlation between the BRAF V600E mutation and long term survival of PTC patients, including OS and RFS. As we known that, the present meta-analysis is initially implemented to evaluate the correlation between the BRAF V600E mutation and long term survival of PTC patients. Although there have no consistent opinions about whether or not the BRAF V600E mutation statue of PTC patients correlated with poor long term survival (OS and/or RFS). After pooled survival data of included articles, we found that the BRAF V600E mutation statue of PTC patients (either Asian or Caucasian) significantly predicts poor survival outcomes (both OS and RFS).
Several mechanisms have been demonstrated to try to explain the poor prognostic role of the positive BRAF V600E mutation statue in PTC patients. First of all, BRAF V600E mutation may result in the excessive activation of RAS/BRAF/MAPK signal pathway, which was believed to act as a critical role in the tumorigenesis and progression of PTC. Animal experiments [25] discovered that normal rat thyroid cells with BRAF V600E mutation were likely to promote tumor invasion by expressing certain gene products and degradating the extracellular matrix of PTC. In addition, researchers also found that the BRAF V600E mutation in PTC was correlated with transportation and metabolism of iodide, and resulted in radioiodine treatment failure [26]. Furthermore, the BRAF V600E mutation induced silence of several tumor-suppressor genes and further promoted the invasiveness of PTC. Xing et al. [27] discovered that the BRAF V600E mutation in PTC was correlated with methylation of following tumor suppressor genes including tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK), and retinoic acid receptor b2 (RARb2).
In addition to the PTC prognosis prediction, the BRAF V600E mutation also has critical value in diagnosis and treatment of PTC patients. A number of studies [28] have demonstrated that the sensitivity, specificity, negative predictive value and positive predictive value of fine-needle aspiration biopsy (FNAB) for PTC were all been significantly improved after combined analysis of BRAF V600E mutation statue. And, some inhibitors have been developed to inhibit the excessive activation of RAS/BRAF/MAPK signal pathway. These inhibitors including sorafenib, PLX4032, RAF265, PLX4720.
In summary, our meta-analysis indicates that the BRAF V600E mutation in PTC is significantly associated with poor survival outcomes including OS and RFS. The BRAF V600E mutation may be used as a prognostic predictor of patients with PTC. However, further large sample size and multicentric clinical researches should be carried out to confirm our findings.
Disclosure of conflict of interest
None.
Authors’ contribution
Study design: Xinguang Qiu, Jianhua Li; Document retrieval: Shuijun Zhang, Shouhua Zheng; Data selection: Jianhua Li, Shuijun Zhang, Danhua Zhang; Wrote the paper: Jianhua Li, Xinguang Qiu.
Supporting Information
References
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