Eur Arch Otorhinolaryngol DOI 10.1007/s00405-013-2872-7
HEAD AND NECK
The association between BRAFV600E mutation and pathological features in PTC Xin Liu • Kangkang Yan • Xuejun Lin • Longyu Zhao • Wenxiu An • Chunpeng Wang Xiaodong Liu
•
Received: 11 August 2013 / Accepted: 19 December 2013 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The BRAFV600E mutation is a common genetic alteration in papillary thyroid carcinoma (PTC) and is associated with some pathological features. The association has been widely reported, but results were inconclusive. In this study a meta-analysis was done to explore the association between BRAFV600E mutation and pathological features in papillary thyroid carcinoma. Medline, PubMed and Web of Science were searched. A total of 69 studies that included 14,170 PTC patients were identified. The outcomes were from 2004 to October 2013. STATA12.0 software package was used to analyze the data. The result was assessed based on pooled odds ratios (ORs) with 95 % confidence intervals (CIs). The results showed that the BRAFV600E mutation was associated with extra-thyroidal extension (OR = 2.09, 95 % CI = 1.69–2.58), advanced TNM stage (OR = 1.90, 95 % CI = 1.62–2.22), lymph node metastasis (OR = 1.68, 95 % CI = 1.41–2.01), multifocality (OR = 1.22, 95 % CI = 1.06–1.40), and recurrence (OR = 2.50, 95 % CI = 1.73–3.59). The meta-
X. Liu K. Yan X. Lin L. Zhao Epidemiology and Statistics, School of Public Health, Jilin University, Changchun, Jilin, China W. An Social Medicine, School of Public Health, Jilin University, Changchun, Jilin, China C. Wang (&) School of Mathematics and Statistics, Northeast Normal University, Changchun, Jilin, China e-mail:
[email protected] X. Liu (&) Key Laboratory of Radiobiology, Ministry of Health, School of Public Health, Jilin University, Changchun 130021, China e-mail:
[email protected]
analysis suggested the potential roles of BRAFV600E mutation in pathological features. BRAFV600E might provide prognostic and diagnostic information for papillary thyroid carcinoma. Keywords BRAFV600E Association Pathological features Papillary thyroid carcinoma Meta-analysis
Introduction Thyroid cancer is the most common endocrine malignancy, accounting for about 1 % of human tumors. Differentiated thyroid carcinoma (DTC) includes the papillary thyroid carcinoma (PTC) and follicular histotypes and their variants, accounting for more than 90 % of all thyroid cancers [1]. PTC is the most common one, characterized by slow growth and long existence. For PTC shares some pathological features in common with other benign thyroid tumors, the diagnostics mainly depend on B ultrasound and biomarkers. Immunohistochemical or molecular biological approaches must be combined with current cytological diagnostic techniques for the diagnosis of PTC [2]. Hughes DT found that central neck lymph node dissection contributed to the treatment of PTC in cases of recurrent disease [3]. BRAF, a cytoplasmic serine-threonine protein kinase, plays a critical role in cell signaling as an activator within the mitogen-activated protein kinase (MAPK) pathway. V600E transversion is the most common BRAF mutation and has been found in 44 % PTC. BRAFV600E can initiate follicular cell transformation, BRAFV600E detection is important for the diagnostic and prognostic management of PTC and can provide diagnostic information [4–9]. But Nam JK claimed that the effect of BRAFV600E detection for
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prediction of poor prognosis of PTC was not clear [10]. Elisei thought that the BRAFV600E positive (BRAFV600E mutation present) cases had a 4.18-fold increase in risk of advanced TNM stage than BRAFV600E negative (BRAFV600E mutation not present) cases [11]. Many studies have evaluated the association between BRAFV600E mutation and pathological features in PTC, but the results are inconclusive and incomplete. To overcome the shortage and to understand the real situation, now a meta-analysis was performed to get a realistic result.
Materials and methods Search strategy, selection criteria and data extraction The following pathological features of PTC were selected to evaluate the possible association with BRAFV600E mutation: (1) extra-thyroidal extension; (2) multifocality; (3) lymph node metastasis; (4) advanced TNM stage; (5) disease recurrence; (6) distant metastasis; (7) age. A comprehensive search strategy was conducted in the PubMed, Medline and Web of Science from 2004 to October 2013. Search terms included ‘‘papillary thyroid carcinoma’’, ‘‘PTC’’, ‘‘BRAFV600E’’, ‘‘BRAFT1799A, synonym of BRAFV600E’’, ‘‘mutation’’, ‘‘papillary thyroid carcinoma’’. The retrieval of literature was performed by two independent reviewers. The studies meeting the following criteria were accepted: (1) the study must offer detailed information about BRAFV600E mutation and pathological features; (2) all cases were diagnosed by hospital; (3) BRAFV600E mutations were determined by direct sequencing; (4) when multiple publications reported on the same or overlapping data, we used the most recent or largest population; (5) publication language was English. The following information was extracted: first author, country, publishing year, the information about BRAFV600E positive cases and BRAFV600E negative cases. If there was disagreement between the two reviewers, a third reviewer was involved to make the decision. Statistical analysis Pooled ORs with 95 % CIs were used to evaluate the association between pathological features and BRAFV600E mutation. Chi square test and I-square were used to assess the heterogeneity. The random effects model or fixed effects model was selected to analyze the result on the heterogeneity of the studies. If the P value\0.10 or I2 [ 50 %, the heterogeneity was defined. Subgroup analyses were performed to analyze the country effect if the heterogeneity was significant. The potential publication bias was assessed using Begg’s funnel plot and Egger’s test. A P value of 0.05 for
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Fig. 1 The process of study selection
Egger’s was considered significant. STATA12.0 software package was used to calculate the result.
Results The characteristics of eligible studies All studies retrieved were carefully screened and 69 studies [5, 7–74] met the criteria, among which 14,170 PTC cases were included (Fig. 1). The main characteristics of 69 studies are shown in Table 1. If the study was conducted by different universities or hospitals, the multi-institutional studies were determined. The studies of Sykorova V, Ulisse S, and Fugazzola L were multi-institutional studies [29, 34, 58]. Of the 69 studies, 37 studies evaluated the association of BRAFV600E mutation with extra-thyroidal extension; 45 studies evaluated the association of BRAFV600E mutation with advanced TNM stage; 49 studies evaluated the association of BRAFV600E mutation with LNM; 38 studies evaluated the association of BRAFV600E mutation with multifocality; 30 studies evaluated the association of BRAFV600E mutation with age; 9 studies evaluated the association of BRAFV600E mutation with disease recurrence; and 13 studies evaluated the association of BRAFV600E mutation with distant metastasis. Meta-analysis The combined results of this meta-analysis and the heterogeneity test are shown in Table 2. Random effects model
Eur Arch Otorhinolaryngol Table 1 Characteristics of individual studies First author
Country
The institutions where the studies were conducted
Source of PTC
Positive/ PTC
Fugazzola et al. [72]
Italy
Institute of Endocrine Sciences, University of Milan
Ospedale Maggiore IRCCS
18/65
Liu et al. [73]
China
Division of Metabolism, Chang Gung Memorial Hospital
Chang Gung Memorial Hospital
49/105
Kim et al. [46]
Korea
Departments of Internal Medicine, Sciences, Asan Medical Centre, University of Ulsan College of Medicine
Asan Medical Centre
31/60
Jo et al. [71]
Korea
Department of Internal Medicine, Chungnam National University School of Medicine
Chungnam National University Hospital
102/161
RiescoEizaguirre et al. [69]
Spain
Hospital Universitario LaPaz
28/67
Park et al. [14]
Korea
Instituto de Investigaciones Biome0 dicas ‘Alberto Sols’ Consejo Superior de Investigaciones Cientı0 ficas y Universidad Auto0 noma de Madrid Department of Pathology, Seoul National University Bundang Hospital
Seoul National University Bundang Hospital
29/37
Sapio et al. [31]
Italy
Department of Scienze Biomorfologiche e Funzionali, Universita‘ Federico II, Naples
Relevant department at the University of Naples
18/43
Fugazzola et al. [29]
Italy
The endocrine surgery units of the Universities of Milan, Perugia and Pisa (M*)
Endocrine surgery units of the Universities of Milan
99/260
Kim et al. [45]
Korea
Departments of Internal Medicine, Sciences, Asan Medical Centre, University of Ulsan College of Medicine
Asan Medical Centre
149/203
Abrosimov [74]
Russian
Department of International Health and Radiation Research, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences
Russian Academy of Medical Sciences
23/40
Zuo et al. [36]
Japan
The ethical committee of Wakayama Medical University
Kuma Hospital
28/42
Nakayama et al. [53]
Japan
Department of General Surgery, Yokohama City University Hospital
Kanagawa Cancer Center
26/40
Lupi et al. [67]
Italy
Departments of Surgery, University of Pisa
Department of Pathology, University of Pisa
219/500
Goutas et al. [68]
Greek
Histopathology Department, Evgenidion Hospital, University of Athens
Not Available
15/55
Elisei et al. [11]
Italy
Departments of Endocrinology and Metabolism,University Hospital of Pisa
University Hospital of Pisa
38/102
Guan et al. [56]
China
Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine
People’s Hospital in Shenyang
19/38
Frasca et al. [61]
Italy
Sezione di Endocrinologia, Dipartimento Clinico-Sperimentale di Medicina e Farmacologia, Azienda Ospedaliera Universitaria Policlinico, University of Messina
Island of Sicily
125/323
Ito et al. [18]
Japan
Kuma Hospital
Kuma Hospital
242/631
Sheu et al. [37]
Germany
The Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen
University Hospital of Essen
92/221
Moon et al. [51]
Korea
Severance Hospital
Severance Hospital
42/84
Oler et al. [57]
Brazil
Genetic Basis of Thyroid Tumor Laboratory, Division of Genetics, Federal University of Sao Paulo
Hospital Sao Paulo
48/73
Xing et al. [60]
USA
Division of Endocrinology and Metabolism, Departments of Medicine, Pathology, Surgery, and Otolaryngology-Head and Neck Surgery, the Johns Hopkins University School of Medicine
Johns Hopkins Hospital
61/134
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Eur Arch Otorhinolaryngol Table 1 continued First author
Country
The institutions where the studies were conducted
Source of PTC
Positive/ PTC
Gu et al. [63]
China
Department of Endocrine and Metabolic Diseases, Rui-jin Hospital
Shanghai and Zhejiang
42/123
Guan et al. [70]
China
Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine
From Shenyang, Shanghai, and Qingdao
639/ 1032
O’Neill et al. [21]
Australia
Endocrine Surgical Unit, University of Sydney
Local human research ethics committee
60/101
Zerilli et al. [25]
Italy
Department of Genetic, University of Palermo, Palermo
Not Available
13/27
Basolo et al. [7]
Italy
Departments of Surgery, University of Pisa, Pisa
Department of Surgical Pathology, University of Pisa
486/ 1060
Jung et al. [47]
Korea
The Institutional Review Board of Seoul, St Mary’s Hospital, the Catholic University of Korea
Seoul St Mary’s Hospital
162/210
Hwang et al. [41]
Korea
Department of Radiology and Center for Imaging Science, Samsung Medical Center
Not Available
106/135
Sykorova et al. [58]
Czech
The Department of Otorhinolaryngology and Head and Neck Surgery of the Faculty Hospital Motol; Department of Surgery of the 2nd Faculty of Medicine and collected at the Department of Pathologu and Molecular Medicine, Faculty Hospital Motol (M*)
The Department of Otorhinolaryngology and Head and Neck Surgery of the Faculty Hospital Motol; Department of Surgery of the 2nd Faculty of Medicine and collected at the Department of Pathologu and Molecular Medicine, Faculty Hospital Motol
81/242
Smith et al. [49]
Australia
Department of Pathology, Griffith Medical School, Gold Coast, Queensland
Different hospitals in Australia
34/76
Howell et al. [15]
USA
Department of Surgery, University of Pittsburgh, Pittsburgh
Department of Surgery, University of Pittsburgh
86/219
Pelttari [16]
Finland
Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital
Helsinki University Central Hospital
34/51
Bommarito et al. [19]
Italy
The IRB of the University of Palermo
Sicilian Registry of Thyroid Tumors
28/56
Patel et al. [20]
Ukraine
Department of Pediatrics, Uniformed Services University of the Health Sciences
The Center for Endocrine Surgery, Kiev
47/104
Stanojevic et al. [38]
Serbia
The Institute of Oncology and Radiology of Serbia, Belgrade
The Institute of Oncology and Radiology of Serbia
84/266
Kim et al. [44]
Korea
Departments of Internal Medicine, Konkuk University School of Medicine
Konkuk Medical Center
154/169
Joo et al. [66]
Korea
Chungnam National University Hospital, Daejeon, Korea
Not Available
79/148
Guerra et al. [12]
Italy
The Ospedale S. Paolo and Fondazione IRCCS Ca’Granda
Fondazione IRCCS Ca’Granda
62/168
Moon et al. [17]
Korea
Department of Radiology, Konkuk University School of Medicine
Not available
141/164
Chakraborty et al. [5]
India
Radiation Medicine Centre, Tata Memorial Hospital
Tissue Repository of Tata Memorial Hospital
46/86
Ahn et al. [22]
Korea
Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, Kyungpook National University Hospital
Not Available
85/107
Lee [24]
Korea
Samsung Medical Center
Samsung Medical Center
403/605
Kurtulmus et al. [26]
Turkey
Department of Endocrinology, Acibadem Maslak Hospital
The thyroid disease clinic of the authors
43/109
Kim et al. [8]
Korea
Seoul National University Hospital
Seoul National University Hospital
381/547
Zheng et al. [9]
China
Tianjin Medical University Cancer Institute and Hospital
Tianjin Medical University Cancer Institute and Hospital
263/512
Lee et al. [28]
Korea
Thyroid Nodule Clinic of the Samsung Medical Center
Samsung Medical Center
342/429
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Eur Arch Otorhinolaryngol Table 1 continued First author
Country
The institutions where the studies were conducted
Source of PTC
Positive/ PTC
Jeong et al. [30]
Korea
Department of Pathology, Soonchunhyang University College of Medicine
Korea cell line bank
178/200
Lee et al. [32]
Korea
The Center for Endocrine Surgery, Chungnam National University Hospital, Daejeon
Chungnam National University Hospital
123/166
Koperek et al. [33]
Austria
Department of Clinical Pathology of the Medical University of Vienna
Medical University of Vienna
76/144
Ulisse et al. [34]
Italy
The Department of Surgical Sciences, ‘Sapienza’ University of Rome; The Department of Medical and Surgical Sciences, University of Padova (M*)
‘Sapienza’ University of Rome
44/91
Nam et al. [10]
Korea
The Institutional Review Board of the Seoul St. Mary’s Hospital, Catholic University of Korea
Seoul St. Mary’s Hospital
335/424
Lee et al. [35]
USA
The Johns Hopkins Hospital
The Johns Hopkins Hospital
44/63
Park et al. [39]
Korea
Departments of Surgery, College of Medicine, The Catholic University of Korea
Seoul St. Mary’s Hospital
152/181
Finkelstein et al. [40]
USA
Departments of Pathology, Hartford Hospital, Hartford
Not Available
34/56
Wang et al. [42]
China
The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou
First Affiliated Hospital, Zhejiang University School of Medicine
115/208
Zheng et al. [43]
China
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital
Tianjin Medical University Cancer Institute and Hospital.
36/86
Kang et al. [54]
Korea
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine
Not Available
226/299
Yim et al. [55]
Korea
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine
Asan Medical Center
17/35
Elisei et al. [11]
Italy
Departments of Endocrinology and Metabolism, University of Pisa
Department of Endocrinology of Pisa University
106/319
Pyo et al. [13]
Korea
Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul
Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine
110/122
Jeong et al. [23]
Korea
Department of Pathology, Soonchunhyang University College of Medicine
Korea cell line bank
189/211
Virk et al. [27]
USA
Department of Pathology, Yale School of Medicine
Yale New Haven Hospital
90/129
Zagzag et al. [48]
USA
Department of Surgery, Division of Endocrine Surgery, New York University School of Medicine, New York
New York University Langone Medical Center
25/37
Ito et al. [50]
Japan
Department of Surgery, Kuma Hospital
Lived in Japan
281/766
Kang et al. [52]
Korea
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine
Samsung Medical Center
118/159
Kleiman et al. [59]
USA
New York Presbyterian Hospital – Weill Cornell Medical College, Department of Surgery, Division of Endocrine and Minimally Invasive Surgery, New York
Not Available
24/47
Kang et al. [64]
Korea
Department of Laboratory Medicine, Chosun University Medical School
Gangnam Severance Hospital
77/100
Fernandez et al. [65]
Italy
Sant’Orsola–Malpighi Hospital of Bologna
University Hospital of Bologna
173/297
M* the study is multi-institutional study
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Eur Arch Otorhinolaryngol Table 2 Meta-analyses of association between pathological features and BRAFV600E mutation OR (95 % CI)
P*
P**
Model selection
[45 versus B45 (30 studies)
1.00 (0.86, 1.17)
0.033
0.052
Random effects model
Asian (14 studies)
1.03 (0.80, 1.32)
Caucasian (11 studies)
0.88 (0.73, 1.06)
Advance TNM stage (44 studies)
1.90 (1.62, 2.22)
0.000
0.070
Random effects model
Asian (24 studies)
1.60 (1.31, 1.95)
Caucasian (15 studies)
2.29 (1.80, 2.91)
Disease recurrence (9 studies)
2.50 (1.73, 3.59)
0.160
0.491
Fixed effects model
Distant metastasis (13 studies)
1.09 (0.55, 2.15)
0.033
0.073
Random effects model
Asian (7 studies)
1.84 (1.12, 3.01)
Extra-thyroidal extension (37 studies)
2.09 (1.69, 2.58)
0.000
0.670
Random effects model
Asian (19 studies)
1.76 (1.36, 2.29)
Caucasian (11 studies)
2.66 (2.06, 3.42)
Lymph node metastasis (49 studies)
1.68 (1.41, 2.01)
Asian (26 studies)
1.55 (1.25, 1.93)
Caucasian (16 studies)
1.73 (1.23, 2.44)
Multifocality (36 studies)
1.22 (1.06, 1.40)
Asian (15 studies)
1.21 (0.99, 1.48)
Caucasian (15 studies)
1.24 (0.97, 1.59)
Discussion 0.000
0.011
0.666
0.228
Random effects model
Random effects model
P* value for heterogeneity P** value for Egger’s test
was selected for extra-thyroidal extension, LNM, advanced TNM stage, multifocality, distant metastasis, and age (for extra-thyroidal extension, P of heterogeneity was 0.000; for LNM, P of heterogeneity was 0.000; for advanced TNM stage, P of heterogeneity was 0.000; for multifocality, P of heterogeneity was 0.011; for distant metastasis, P of heterogeneity was 0.033; and for age, P of heterogeneity was 0.033). Fixed effects model was selected for disease recurrence (for disease recurrence, P of heterogeneity was 0.160). Overall, there were statistical associations between the BRAFV600E mutation and extra-thyroidal
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extension (OR = 2.09, 95 % CI = 1.69–2.58), advanced TNM stage (OR = 1.90, 95 % CI = 1.62-2.22), lymph node metastasis (LNM) (OR = 1.68, 95 % CI = 1.41–2.01), multifocality (OR = 1.22,95 % CI = 1.06–1.40), and recurrence (OR = 2.50, 95 % CI = 1.73–3.59), but the associations were not found between the BRAFV600E mutation and age (OR = 1.00, 95 % CI = 0.86–1.17), distant metastasis (OR = 1.09, 95 % CI = 0.55–2.15). Sensitive analyses were conducted to determine the influence of single study on the overall meta-analysis, and the omission of any study made no difference, indicating that the results were statistically robust. Funnel plots and Begg’s test were performed to access the publication bias. The all Begg’s funnel plots did not show obvious asymmetry (Begg’s funnel plots not shown), and the results of Egger’s test were confirmed for the association between BRAFV600E mutation and pathological features (P of Egger’s test is 0.670 for extra-thyroidal extension; 0.228 for multifocality; 0.666 for lymph node metastasis; 0.070 for advanced TNM stage; 0.491 for disease recurrence; 0.073 for distant metastasis; 0.052 for age). The results of Begg’s funnel plot and Egger’s test did not show the publication bias.
Sixty-nine studies including 14,170 PTC cases from 2004 to October 2013 were used to explore the association between BRAFV600E mutation and pathological features in PTC. This meta-analysis suggested that extra-thyroidal extension, multifocality, LNM, disease recurrence, and advanced TNM were associated with BRAFV600E mutation in PTC. Kim et al. [75] once made a similar meta-analysis; his studies were from 2003 to 2010, but there were only three studies in 2010. He found that extra-thyroidal invasion, LNM, advanced TNM stage, and disease recurrence/persistent were associated with BRAFV600E mutation. Compared with the conclusion of Kim, our study was based on papers from 2004 to October 2013; among the 69 studies, 45 studies were from 2010 to 2013. This study not only compared the associations of BRAFV600E mutation and extra-thyroidal extension, LNM, advanced TNM stage, disease recurrence/persistent, but also evaluated the associations of BRAFV600E mutation and multifocality, distant metastasis. The results about the associations of BRAFV600E mutation and extra-thyroidal extension, LNM, advance TNM stage, disease recurrence were consistent. The incidence of BRAFV600E mutation ranged from around 27.3 to 90.2 %, and the average prevalence rate of BRAFV600E mutation was 56.3 % in this sdudy. Some pathological features are the risk factors of PTC. Recently,
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Fig. 2 Forest plot for the association between BRAFV600E mutation and extra-thyroidal extension (a), age (b), disease recurrence (c), distant metastasis (d), lymph node metastasis (e), multifocality (f), advanced TNM stage (g). ORs with corresponding 95 % CIs of
individual studies for association BRAFV600E mutation associated with extra-thyroidal extension are shown in the figure. The forest plot displays the effect size and 95 % CIs for each study and overall
some scientists have found the correlations of BRAFV600E mutation with nodal metastasis, extra-thyroidal invasion, higher risk of recurrent and advanced TNM stage. The studies of Howell GM and Lee JI agreed that there were associations between advanced TNM stage and BRAFV600E mutation [15, 24]. The classic PTC (CPTC) and the follicular variant of PTC (FVPTC) are the most frequently diagnosed variants. CPTC and FVPTC present distinct cytoarchitectural features. Eloy C separately compared the risk factors of BRAFV600E mutation for CPTV and FVPTC [76]; the results were consistent between the two groups. BRAFV600E mutation status can identify the risk of central
compartment lymph node metastasis (CLNM). BRAFV600E mutation could predict the CLNM in PTC and could guide the extent of initial surgery. Besides above-mentioned pathological features, a few researchers evaluated the associations between BRAFV600E mutation and other pathological features; they found no association between BRAFV600E mutation and lymphatic invasion [8, 35]. Elisei R studied 102 PTC patients with a median follow-up of 15 years, which demonstrated a significant correlation between the BRAFV600E mutations and a worse outcome of patients with PTC [11]. Ito et al. [18] reported that there existed differences between Japan and some Western
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Fig. 2 continued
countries on BRAFV600E mutation. For Koreans, the prevalence of the BRAFV600E mutations in PTC is high, and iodine-rich diet might be one possible reason [9]. From Fig. 2 we found that the association between the
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BRAFV600E mutations and distant metastasis is stable and credible, the BRAFV600E mutations might provide diagnostic information of distant metastasis for papillary thyroid carcinoma.
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The average prevalence rate of the disease recurrence is 12.89 % for PTC patients, 15.63 % for group of BRAFV600E mutation, and 9.38 % for group of BRAFV600E wild. The meta-analysis illustrated that there was an association between BRAFV600E mutation and disease recurrence (OR = 2.50, 95 % CI = 1.73-3.59), suggesting that the PTC in patients with BRAFV600E mutation was more dangerous in disease recurrence than in the PTC patients without BRAFV600E mutation. Some studies made survival analysis to explore the differences in recurrencefree survival in PTC patients with BRAFV600E mutation versus BRAFV600E wild type. Tae YK made a Kaplan– Meier survival analysis and founded that the cumulative survival was different between BRAFV600E positive and BRAFV600E negative (P = 0.037) [45], the cumulative survival of BRAFV600E negative patients was higher than that of BRAFV600E positive. Xing et al. got the same conclusion [60], while the conclusion of Lee JI [24] was different from Tae YK. The Kaplan–Meier survival analysis of Ji et al. proved that there was no difference in tumor persistence/recurrence-free between PTC patients with and without the BRAFV600E mutation (P = 0.095), and the tumor persistence/recurrence-free survival at 24 months of PTC patients with BRAFV600E mutation was not different from those without BRAFV600E mutation (P = 0.259). Ulisse S also made a Kaplan–Meier survival analysis, and the PTC patients were followed up from 6 to 64 months, he failed to identify difference of cumulative survival between BRAFV600E positive and BRAFV600E negative (P = 0.9375) [34]. Stanojevic et al. [38] got the same conclusion. Thus, more studies were needed to get the correct conclusion. Some researches have proved the association between BRAFV600E mutation and prognosis. Costa AM illustrated BRAF ‘alone’ did not represent a marker for prognosis [77]. Elisei et al. [11] drew the opposite conclusion and proved the BRAF mutation was demonstrated to be a prognostic factor independent from other pathological features. Whether BRAF can be used as independent factor for prognosis is controversial. Subgroup analyses of patient’s country were performed to explore possible causes of heterogeneity. When the number of studies was more than five and the number of PTC patients was more than 1,000, we would explore the influence of geographical regions, which could make the conclusion more credible. There was no association between BRAFV600E mutation and distant metastasis, but in subgroup analyses, the association was found in Asian. There was association between multifocality and BRAFV600E mutation in pooled meta-analysis, but the association was not found in Asian and Caucasian. The above two different conclusions might be caused by the ethnicity or geographical regions. The other conclusions of subgroup analysis were consistent with the pooled meta-analysis.
Some limitations should be considered when interpreting the conclusion. Firstly, the number of cases in some studies was small, so the related studies could not provide strong evidence about the results [14, 25, 31, 55, 74]. Secondly, subgroup analyses were restricted because of inadequate information. Thirdly, the selection of BRAFV600E negative cases and BRAFV600E positive cases was not random, which could cause selection bias. In conclusion, our meta-analysis suggested that extrathyroidal extension, lymph node metastasis, disease recurrence, and advanced TNM stage were associated with BRAFV600E mutation. Large well-designed studies should be necessary to explore the association between BRAFV600E mutation and other pathological features. Acknowledgments This study was supported by Jilin Provincial Science and Technology Development Project (Grant No. 201205008), Science and Technology Project of the Department of Health of Jilin Province (Grant No. 2013Z034) and Postdoctoral Scientific Research Project of Jilin Province (Grant No. RB201343).
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