Received: 21 January 2023 Revised: 26 March 2023 Accepted: 26 May 2023

DOI: 10.1111/jop.13458

REVIEW

Does BRAF V600E mutation affect recurrence rate of

ameloblastomas? Systematic review and meta-analysis

Allan Vinícius Martins-de-Barros 1,2 | Caio César Gonçalves Silva 1,3 |

1,3
Kalyne Kelly Negromonte Gonçalves |
Renata de Albuquerque Cavalcanti Almeida 1,3 | Emanuel Dias de Oliveira e Silva 1,3 |
Fábio Andrey da Costa Araújo 1,3 | Liam Robinson 4 | Willie F. P. van Heerden 4 |
Marianne de Vasconcelos Carvalho 1,2

1
School of Dentistry, Post-Graduation
Program in Dentistry, University of Abstract
Pernambuco (UPE), Recife, Pernambuco, Brazil
Objective: The objective of this systematic review with meta-analysis was to critically
2
Centro Integrado de Anatomia Patolo
gica
(CIAP), Hospital Universitário Oswaldo Cruz evaluate the available data on the association of the BRAF V600E mutation and recur-
(HUOC/UPE), Recife, Pernambuco, Brazil rence rate of ameloblastomas.
3
Department of Oral and Maxillofacial Surgery,
Materials and Methods: This systematic review was registered in Prospero
Hospital Universitário Oswaldo Cruz (HUOC/
UPE), Recife, Pernambuco, Brazil (CRD42020183645) and performed based on the PRISMA statement. A comprehen-
4
Department of Oral and Maxillofacial sive search in PubMed, Web of Science, Scopus and Cochrane Library databases was
Pathology, School of Dentistry, Faculty of
Health Sciences, University of Pretoria,
performed in order to answer the question “Does BRAF V600E mutation affect recur-
Pretoria, South Africa rence rate of ameloblastomas?” Methodological quality and risk of bias of the

Correspondence
selected studies were assessed with JBI Critical Appraise Tool. Meta-analysis of
Fábio Andrey da Costa Araújo, School of quantitative data was conducted with RevMan 5.3 and Jamovi 2.3.
Dentistry, Department of Oral and
Maxillofacial Surgery, University of
Results: The initial search identified 302 articles, and 21 met the inclusion criteria. A
Pernambuco, Rua Arno
bio Marquês, total of 855 subjects with ameloblastoma were included in the analysis. The pooled
310, Santo Amaro, Recife, Pernambuco, Brazil.
measures for frequency of BRAF V600E mutation was 65.30% (95% CI: 0.56–0.75;
Email: fabio.andrey@upe.br
p < .001; I2 = 90.85%; τ = 0.205; p < .001), and the pooled recurrence rate was
Funding information
25.30% (95% CI: 0.19–0.31; p < .001; I2 = 79.44%; τ = 0.118; p < .001). No differ-
Coordenação de Aperfeiçoamento de Pessoal
de Nível Superior; Fundação de Amparo à ences in recurrence rate were observed between the BRAF V600E and wild type
Ciência e Tecnologia do Estado de
Pernambuco
BRAF ameloblastomas, with a pooled Odds Ratio of 0.93 (95% CI: 0.56–1.54;
p = .78; I2 = 31%; p = .09).
Conclusions: BRAF V600E mutation is a frequent event in ameloblastomas, but does
not increase nor reduce its recurrence rate, and thus have a limited value in predict-
ing its prognosis.

KEYWORDS
ameloblastoma, BRAF V600E, odontogenic tumors, proto-oncogene proteins b-raf, systematic
review

J Oral Pathol Med. 2023;52:701–709. wileyonlinelibrary.com/journal/jop © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 701

702
1 | I N T RO DU CT I O N
Ameloblastoma is one of the most common odontogenic tumors.
Despite being a benign neoplasm derived from odontogenic epithe-
lium, it has a locally aggressive and infiltrative growth pattern.1,2 The
World Health Organization classifies ameloblastoma into five variants:
conventional, unicystic, peripheral, adenoid and metastasizing. Micro-
scopically, it is composed of ameloblast-like tumor islands with central
stellate reticulum-like cells arranged in patterns that vary from entirely
solid to variably cystic.3 Due to its aggressiveness, ameloblastomas
show a markedly high tendency for local recurrence even after radical
surgical treatment.4
Mutations related to the Mitogen-activated protein kinase
(MAPK) pathway are known to participate in the pathogenesis of
5–7
many epithelial tumors. Recent studies found a large number of
ameloblastomas harboring activating mutations in the RAF proto-
oncogene, responsible for encoding a serine/threonine kinase that
plays an important role in cell cycle regulation through MAPK
8,9
pathway.
The majority of the mutations in the RAF gene are missense and
result in a valine (V) to glutamic acid (E) substitution at codon 600.
The so-called BRAF V600E mutation leads to the codification of an
altered protein, which works in the MAPK pathway as a permanently
activated RAF protein, dysregulating cell signaling in processes such
as growth, proliferation, and diferentiation.6,7
Currently, few studies suggest that the presence of the BRAF
V600E mutation in ameloblastomas is associated with tumor size,
location, and aggressiveness.10–12 However, it is still not clear
whether the BRAF V600E mutation correlates with the biological
behavior and recurrence rate of ameloblastomas. In this context, the
objective of this study is to systematically review the literature
regarding the association of the BRAF V600E mutation with the
recurrence rate of ameloblastomas.
2 | MATERIALS AND METHODS
2.1 | Protocol and registration
This systematic review was performed and structured based on the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA)13 statement and registered in PROSPERO under registry
CRD42020183645.
2.2 | Data sources and search strategy
A comprehensive search of studies published until November
10, 2022 in the Medline/PubMed, Web of Science, Scopus, and
Cochrane Library databases was performed individually by two
authors (AVMB and CCGS) using a combination of free-text and
DeCS/MeSH terms as follows: (“proto-oncogene proteins b-raf” OR
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MARTINS-DE-BARROS ET AL.
“BRAF” OR “V600E”) AND (“odontogenic tumors” OR “ameloblas-
toma”). After the removal of duplicates, the authors listed and
screened the publications according to the title and abstracts and
evaluated them for eligibility. Disagreements were analyzed by a third
author (MVC) and a consensus reached by discussion. In addition,
studies in the reference list of the selected articles were searched
manually by the same authors to identify additional articles that could
have been missed in the initial search.
2.3 | Study selection and eligibility criteria
The eligibility criteria for selection of the studies for this review met
the criteria established by the PECO (population, exposure, control,
and outcomes) approach based on the following research question:
“Does BRAF V600E mutation affect the recurrence rate of ameloblas-
tomas?” According to the PECO criteria, the population was set as
subjects with ameloblastoma, the exposure was BRAF V600E muta-
tion, and subjects with wild-type BRAF ameloblastoma were used for
comparison. The main outcome was the recurrence rate. The relative
frequency of BRAF V600E mutations was considered as an additional
secondary outcome.
Cross-sectional studies, cohort studies, case–control studies, and
case-series published in English were included in this review. No time
restrictions were established. Animal studies, single case reports,
reviews, studies reporting previously published or duplicate data, and
studies that did not report recurrence rate or BRAF V600E mutational
status of the tumors were excluded.
Cohen's κ coefficient was used to calculate the inter-rater agree-
ment during the inclusion of publications, with an almost perfect level
of agreement between the authors AVMB and CCGS (κ = 0.90).
2.4 | Data extraction
The selection of studies and extraction of data were carried out by
two researchers (AVBM and CCGS). The extracted data were sorted
as quantitative or qualitative, tabulated, and verified by all
researchers. Any disagreement was resolved by a third person (MVC)
with experience in oral and maxillofacial pathology. The following data
was identified and extracted from each article: authorship; year of
publication; study design; sample size; age and sex of the patients;
tumor location; clinicopathological variant and histological subtype
according to 5th WHO Classification of Head and Neck Tumors3;
treatment; history of recurrence; follow-up; frequency of BRAF V600E
mutation; and methods used for BRAF V600E mutation detection.
When two or more methods were simultaneously used for mutation
detection, the results of the gold standard molecular tests14
(e.g., DNA sequencing, allele-specific qPCR) were adopted as the ref-
erence tests for statistical purposes. In case of missing information,
the corresponding authors were contacted via email to request raw
data for analysis.

MARTINS-DE-BARROS ET AL.
2.5 | Methodological quality and risk of bias
assessment
The methodological quality and risk of bias of the selected articles
were assessed using the Joanna Briggs Institute (JBI) Critical Appraisal
Tool for Cohort Studies,15 performed by two researchers (CCGS and
KKNG). This tool consists of eleven questions with four possible
answers each: “yes” (low risk of bias); “no” (high risk of bias);
“unclear” (unclear risk of bias); and “not applicable.” Disagreements
between the researchers were discussed and resolved by consensus.
The risk of bias was ranked as “high” when the study reached less
than 50% of positive answers, “moderate” when the study reached
50%–69% of positive answers, and “low” when the study reached
70% or more of positive answers in tool questions.
2.6 | Summary measures and synthesis of results
Qualitative data were analyzed and presented in the form of text and
tables. Meta-analysis of quantitative data was conducted with appropri-
ate softwares systems, RevMan 5.3.5 (The Cochrane Collaboration,
Copenhagen, Denmark) and Jamovi 2.3 (The Jamovi Project, Sydney,
Australia), using a random-effects model. The odds ratio (OR) was calcu-
lated by applying the Mantel–Haenszel method to estimate the chance
of tumor recurrence, considering a 95% confidence interval (95% CI).
Pooled frequency for BRAF V600E mutations and for tumor recurrence
were calculated using the restricted maximum-likelihood method. Studies
that reported sufficient data on “clinicopathological variant” and “treat-
ment modality” were stratified and included in additional meta-analyses.
Heterogeneity was assessed by Higgins inconsistency (I2), Chi-
square test, Tau and prediction interval.
3 | RESULTS
3.1 | Literature search
The initial search of the databases identified 302 articles, including
100 in PubMed, 102 in Scopus, 99 in Web of Science, and 01 in the
Cochrane Library. Duplicate references were removed and the remaining
titles and abstracts analyzed. Forty-six articles were selected for full-text
analysis, with 219,10,12,16–33 studies meeting the criteria to be included in
this systematic review. The PRISMA flow diagram showing the complete
article selection process is illustrated in Figure S1.
3.2 | Methodological quality and risk of bias
assessment of selected studies
The methodological quality and risk of bias assessment based on the
Joanna Briggs Institute (JBI) critical appraisal tool for analytical cohort
studies is shown in Figure S2. Five out of the 21 studies (23.81%) were
categorized as low risk of bias, while 10 studies (47.62%) presented with
a moderate risk of bias and six studies (28.57%) with a high risk of bias.
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703
The most common methodological fragilities in the assessed stud-
ies were the identification and definition of strategies dealing with
confounding factors that might have influenced the main outcome as
well as the lack of reporting data on follow-up time.
3.3 | Description of the studies
Tables 1 and 2 display the detailed description of the included studies.
Data from 21 observational studies published between 2014 and
2022 were analyzed in this systematic review. Only one of them was
conducted with a prospective methodological design, while the other
20 studies were retrospective. Most of the studies were conducted
with Brazilian (5/21) or Japanese (4/21) populations and two studies
were international collaborations. Figure S3 shows the geographic dis-
tribution of the included studies.
A total of 855 subjects with ameloblastoma were included in the
analysis: 581 (67.95%) harboring BRAF V600E mutations and
274 (32.05%) with wild-type BRAF. The most common clinicopatho-
logical variants were conventional (84.32%) and unicystic types
(13.80%). Only nine adenoid, six peripheral, and one metastasizing
ameloblastoma were included. The tumors were more frequent in
men, with a male-to-female ratio of 1.27:1, occurring mostly in the
fourth and fifth decades of life (Table 1).
Mandibular ameloblastomas accounted for more than 80% of the
cases (692/855). The frequency of BRAF V600E mutations was found
to be higher in mandibular ameloblastomas compared to maxillary
ameloblastomas, 74.27% and 38.99%, respectively (Table 1).
Data on treatment modality were described in only eight studies:
181 (51.34%) patients received radical treatment (surgical resection),
and 167 (48.64%) patients underwent conservative treatment (surgi-
cal enucleation). There was a similar distribution in BRAF V600E and
wild-type BRAF groups (Table 2).
Recurrence was reported in 210 out of 811 cases, with a crude
recurrence rate of 25.89%. BRAF V600E mutations were detected in
140 (66.67%) recurrent ameloblastomas, while the other 70 (33.33%)
were wild-type BRAF. Eight studies reported data on follow-up time,
which varied widely from <1 to 514 months (Table 2).
Statistical analysis to assess the association between BRAF muta-
tional status and events of recurrence in ameloblastomas was per-
formed in 13 out of 21 studies. Eight of them showed no association
between BRAF mutational status and tumor recurrence. The main
findings on BRAF V600E mutational association with recurrence out-
comes is detailed in Table 2.
3.4 | Meta-analysis of outcomes and summary
measures for recurrence rates
The overall pooled measures, as quantified by random effects meta-
analysis, indicated a frequency of 65.30% for BRAF V600E mutations
in ameloblastomas (95% CI: 0.56–0.75; p < .001; I2 = 90.85%;
τ = 0.205; p < .001), as shown in Figure S4.

704
FIGURE 1 Forest plot graphs of meta-analysis of recurrence rates in BRAF V600E mutated and wild-type BRAF ameloblastomas.
The pooled recurrence rate was 25.30% (95% CI: 0.19–0.31;
p < .001; I2 = 79.44%; τ = 0.118; p < .001) (Figure S5). No differences in
recurrence rate were observed between the BRAF V600E mutated and
wild-type BRAF ameloblastomas, with a pooled (Mantel–Haenszel) OR of
0.93 (95% CI: 0.56–1.54; p = .78; I2 = 31%; p = .09) (Figure 1).
In the clinicopathological variant meta-analysis, seventeen
studies with 626 conventional ameloblastomas and nine studies
with 87 unicystic type ameloblastomas reported recurrence data
and were therefore included for analysis. No association between
BRAF mutational status and recurrence rate was observed either
for conventional (OR = 1.08; 95% CI: 0.58–1.99; p = .81;
I2 = 33%; p = .10) nor for unicystic (OR = 1.48; 95% CI: 0.28–
7.88; p = .65; I2 = 0%; p = .86) variants (Figure S6). In view of the
limited number of cases, it was not possible to perform a separate
meta-analysis for the other ameloblastoma variants: adenoid,
peripheral, and metastasizing.
Additionally, no association between BRAF mutational status and
recurrence rate was observed independently of the treatment modal-
ity, as evidenced by the meta-analysis including six studies with
126 cases of ameloblastoma treated radically (OR = 1.18; 95% CI:
0.45–3.06; p = .74; I = 8%; p = .37) and five studies with 90 cases
2
that received conservative treatment (OR = 0.84; 95% CI: 0.27–2.67;
p = .77; I = 0%; p = .64), as seen in Figure S6.
2
4 | DISCUSSION
Prognosis prediction in ameloblastomas has long been the subject of
academic debate as it impacts clinical decisions regarding tumor man-
34
agement. Although many clinical and molecular parameters have
been suggested as possible factors associated with the risk of
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MARTINS-DE-BARROS ET AL.
recurrence in ameloblastomas, their applications in clinical practice are
still limited.10,35
Recent identification of high frequencies of BRAF V600E muta-
tions in ameloblastomas highlights the debate on whether this molec-
ular alteration could affect the clinical behavior, progression, and
recurrence capability of these tumors and, thus, whether it could be
used as a reliable prognostic marker.8–10,18,34 In this context, this sys-
tematic review and meta-analysis summarizes the current evidence on
the association between BRAF V600E mutational status and recur-
rence rate in ameloblastomas.
Due to the disturbing effects of BRAF activating mutations in the
MAPK signaling pathway,36 many studies hypothesized that amelo-
blastomas harboring BRAF V600E mutations would be more aggres-
sive and would have higher recurrence rates than wild-type BRAF
ameloblastomas.8–12,17–31 However, the overall results were inconclu-
sive and varied widely among the studies.
In parallel, the prognostic implications of BRAF V600E mutations
in neoplasms other than ameloblastomas are not uniform nor fully
understood. Many studies suggest that the BRAF V600E mutation
serves as an independent risk factor for recurrence, local aggressive-
ness, and lymph node metastasis in cases of papillary thyroid
carcinoma.37–39 In contrast, the same does not apply when it comes
to other tumors such as melanomas, where BRAF mutational status
does not seem to affect disease recurrence.40–42
The current systematic review and meta-analysis showed no dif-
ference in recurrence rates regardless of BRAF mutational status in
cases of ameloblastoma. For this reason, although BRAF V600E muta-
tion can be considered a tumor marker with promising applications for
diagnostic and therapeutic purposes,43,44 it seems to have a very lim-
ited value in predicting the recurrence of ameloblastomas, especially
in conventional and unicystic variants.
 TABLE 1 Detailed description of BRAF V600E mutation frequency and clinicopathological variables of ameloblastomas in the studies included in the systematic review.

Sex Location Clinicopathological variant

MARTINS-DE-BARROS ET AL.

Men Women Maxilla Mandible Conventional Unicystic Peripheral Metastasizing Adenoid

Frequency of
Author and year of Sample BRAF V600E Mean age BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF
publication size mutation (%) (YEARS) V600E WT V600E WT V600E WT V600E WT V600E WT V600E WT V600E WT V600E WT V600E WT

Bastos et al. (2022) 9 0.00 47.66 0 7 0 2 0 7 0 2 0 0 0 0 0 0 0 0 0 9

a
Bonacina et al. (2022) 74 55.40 47.90 29 17 12 16 3 12 38 19 24 27 16 4 1 2 0 0 0 0

Brown et al. (2014) 84 64.28 41.29 31 16 23 14 3 13 51 17 48 29 5 0 0 1 1 0 0 0

Derakhshan et al. 50 92.00 42.80 27 2 19 2 5 0 40 4 46 4 0 0 0 0 0 0 0 0

(2020)b

Diniz et al. (2015) 17 82.35 30.20 7 2 7 1 3 1 11 2 9 2 5 1 0 0 0 0 0 0

Duarte-Andrade et al. 11 81.81 34.63 5 2 4 0 0 1 9 1 9 2 0 0 0 0 0 0 0 0

(2019)

Fregnani et al. (2016) 73 46.57 34.70 17 18 17 21 32 31 2 8 34 39 0 0 0 0 0 0 0 0

Fuji et al. (2022) 38 65.78 38.55 13 11 12 2 3 4 22 9 21 10 4 3 0 0 0 0 0 0

Heikinheimo et al. 78 76.92 38.38 27 12 33 6 2 3 58 15 28 11 32 7 0 0 0 0 0 0

(2019)

Kelppe et al. (2019) 36 72.22 51.90 12 8 14 2 0 7 26 3 18 9 7 0 1 1 0 0 0 0

Kokubun et al. (2022) 24 83.33 37.79 10 2 10 2 0 0 20 4 17 3 3 1 0 0 0 0 0 0

Kondo et al. (2020) 9 77.77 40.11 3 1 4 1 0 0 7 2 7 2 0 0 0 0 0 0 0 0

Kunmongkolwut et al. 74 67.56 34.20 30 10 20 14 5 2 45 22 50 24 0 0 0 0 0 0 0 0

(2022)

Marcelino et al. (2021 128 82.03 31.39 61 10 44 13 0 0 105 23 90 20 15 3 0 0 0 0 0 0

Oh et al. (2019) 30 90.00 38.96 18 1 9 2 2 0 25 3 25 2 2 1 0 0 0 0 0 0

Santana et al. (2020) 30 66.66 32.26 13 3 7 7 3 1 14 12 17 10 3 0 0 0 0 0 0 0

Seki-Soda et al. (2020) 21 76.19 NR 12 3 6 4 0 0 16 5 14 3 2 2 0 0 0 0 0 0

Shirsat et al. (2018) 30 33.33 33.00 6 12 4 8 0 0 10 20 10 20 0 0 0 0 0 0 0 0

Sweeney et al. (2014)c 28 42.85 64.22 4 9 0 5 0 11 11 5 12 16 0 0 0 0 0 0 0 0

Xia et al. (2020) 5 60.00 39.8 0 2 3 0 0 1 3 1 2 1 1 1 0 0 0 0 0 0

You et al. (2018) 6 33.33 45.5 1 1 1 3 1 3 1 1 2 4 0 0 0 0 0 0 0 0

Abbreviations: NR, not reported; WT, wild type.

a
Did not report data for tumor location in two cases.
b
Reported one case with involvement of both the maxilla and mandible.
c
Did not report data for patient sex in 10 cases and for tumor location in 01 case.
705

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 TABLE 2 Detailed description of treatment modality, recurrence outcomes and follow-up data reported by the studies included in the systematic review.
706

Treatment modality Recurrence Follow-up

Radical/ Conservative/
resection enucleation Not reported Yes No Not reported
Main findings on BRAF V600E
Author and year BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF BRAF Mean Range association with recurrence
of publication V600E WT V600E WT V600E WT V600E WT V600E WT V600E WT (months) (months) outcomeS
Bastos et al. NR NR NR NR NR NR 0 4 0 5 0 0 NR NR Statistical analysis for association
(2022) was not performed
Bonacina et al. NR NR NR NR NR NR 11 10 30 23 0 0 NR NR No association between BRAF
(2022) status and recurrence was found
Brown et al. 42 25 6 4 6 1 8 7 46 23 0 0 34,59 0–514 WT BRAF showed lower DFS
(2014) when compared to BRAF V600E
Derakhshan NR NR NR NR NR NR 12 1 34 3 0 0 72 12–204 No association between BRAF
et al. (2020) status and recurrence was found
Diniz et al. NR NR NR NR NR NR 0 0 8 0 6 3 31,5 12–72 Statistical analysis for association
(2015) was not performed
Duarte-Andrade NR NR NR NR NR NR 2 1 7 1 0 0 NR NR Statistical analysis for association
et al. (2019) was not performed
Fregnani et al. 14 17 20 22 0 0 13 2 21 37 0 0 85,4 NR BRAF V600E presented high
(2016) recurrence rates and lower DFS
when compared to WT BRAF
Fuji et al. (2022) NR NR NR NR NR NR 4 4 21 9 0 0 NR NR Statistical analysis for association
was not performed
Heikinheimo 13 8 47 10 0 0 20 7 40 11 0 0 114,77 7–377 WT BRAF showed lower DFS
et al. (2019) when compared to BRAF V600E
Kelppe et al. NR NR NR NR NR NR 9 5 17 5 0 0 NR NR No association between BRAF
(2019) status and recurrence was found
Kokubun et al. 13 2 7 2 0 0 10 1 10 3 0 0 NR NR No association between BRAF
(2022) status and recurrence was found
Kondo et al. NR NR NR NR NR NR 1 0 6 2 0 0 NR NR Statistical analysis for association
(2020) was not performed
Kunmongkolwut 14 9 23 9 13 6 9 7 22 7 19 10 NR 1–300 No association between BRAF
et al. (2022) status and recurrence was found
Marcelino et al. NR NR NR NR NR NR 10 1 95 22 0 0 NR NR No association between BRAF
(2021) status and recurrence was found
Oh et al. (2019) NR NR NR NR NR NR 12 3 15 0 0 0 NR NR No association between BRAF
status and recurrence was found
Santana et al. NR NR NR NR NR NR 7 3 13 7 0 0 NR NR No association between BRAF
(2020) status and recurrence was found
MARTINS-DE-BARROS ET AL.

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 16000714, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jop.13458 by UPE - Universidade de Pernambuco, Wiley Online Library on [27/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MARTINS-DE-BARROS ET AL. 707

Due to the limited number of cases, it was not possible to spe-

recurrence rates than WT BRAF

cifically assess the impact of this mutation in uncommon variants of

Statistical analysis for association

Statistical analysis for association

Statistical analysis for association

Main findings on BRAF V600E

recurrence rates than BRAF

the ameloblastoma, such as peripheral and metastasizing, but it is

BRAF V600E presented high

association with recurrence

WT BRAF presented high

very likely that they follow the same pattern observed for the con-
ventional and unicystic variants. However, it is still unclear whether

was not performed

was not performed

was not performed

mutations in BRAF could affect the risk of distant metastasis in
ameloblastomas, as to date very few metastasizing ameloblastomas
outcomeS

have been assessed for activating mutations in the MAPK pathway.

V600E Further studies with sufficient sample sizes are required in this
regard.
The variant, adenoid ameloblastoma was only recently included
(months)

12–48

10–16
Range

as a separate variant in the 5th edition of the WHO Classification of

NR

NR

NR

Head and Neck Tumors.3 To date, only one study reported data from
this variant, in which all cases were wild-type BRAF.16 For this reason,
Follow-up

(months)

no association with the recurrence rate was possible. Although its

Mean

12,25
NR

NR

NR

pathogenesis remains poorly explored, the molecular signature of the

26

adenoid ameloblastomas, with a marked absence of BRAF V600E

BRAF

mutations and proven beta-catenin mutations, might support its clas-

WT
Not reported

sification as a distinct entity (and not as a variant of ameloblastoma),

as suggested by Bastos et al.16
V600E
BRAF

Some limitations of the present systematic review and meta-

0

analysis must be considered, as many of the included studies pre-

BRAF

sented with a moderate or high risk of bias. One of the most common
WT
3

1
18

methodological fragilities was the lack of identification and definition

of strategies to deal with confounding factors. According to the JBI
V600E
BRAF

Critical Appraisal Tool,15 confounding factors can be defined as a vari-

No

16

able with the potential to distort or mask the effects of the investi-
gated exposure on the main outcomes.
BRAF
WT
2

Therefore, a major confounding factor in studies reporting recur-

Recurrence

rence in ameloblastomas is the treatment modality: higher recurrence

V600E
BRAF

rates are expected for tumors treated conservatively compared to

Yes

radical surgical treatment,4 regardless of BRAF mutational status.

However, only eight studies reported data on the treatment modality,
BRAF
WT
NR

NR

and even fewer studies adjusted their study design and statistical
Not reported

Abbreviations: DFS, disease free survival; NR, not reported; WT, wild type.

analysis to deal with its confounding effects on recurrence outcomes.

V600E

Regardless, the present meta-analysis did not show evidence of any

BRAF

NR

NR

association between BRAF mutational status and recurrence rate,

0

independent of the treatment modality.

BRAF
Conservative/

WT

Another common methodological fragility identified in the

NR

NR
8

2
enucleation

included studies was the lack of reporting data on follow-up time.

V600E

Ameloblastomas are slow-growing benign tumors, and relapse can

BRAF

NR

NR

occur even decades after initial treatment.1 For this reason, short
4

1
Treatment modality

follow-up periods may not be sufficient for recurrence outcomes to

BRAF

occur. Controlling the length of the follow-up is challenging and not

WT
NR

NR
12

always possible in retrospective studies. In this scenario, addressing

resection
Radical/

strategies to deal with this limitation is fundamental to reduce the risk

V600E
BRAF
(Continued)

of bias.15 Among the included studies, only Fregnani et al.10 controlled

NR

NR
6

this variable by setting up a cutoff of 36 months of follow-up as an

Author and year

You et al. (2018)

inclusion criterion for statistical analysis.

Xia et al. (2020)
Seki-Soda et al.

Sweeney et al.
of publication

Shirsat et al.

Although the BRAF V600E mutations seem to be an early event in

TABLE 2

(2020)

(2018)

(2014)

the pathogenesis of ameloblastoma and likely mediate crucial aspects of

tumor growth,7 secondary molecular processes are also implicated in the
progression of the disease, including those related to cell proliferation,

708
tumor invasion, angiogenesis, and bone remodeling.7,34 The influence of
BRAF V600E mutations in these molecular processes remains to be
10,22,25,28,36,45
explored, and have been the focus of recent studies.
In conclusion, BRAF V600E mutations are a molecular event found
in about two-third of ameloblastomas, with very similar frequencies in
recurrent and primary/nonrecurrent tumors. Although it seems to
contribute to the tumor pathogenesis, the BRAF V600E mutation
alone does not increase nor reduce tumor recurrence rate, and thus
have a limited value in predicting overall prognosis in ameloblastomas.
AUTHOR CONTRIBUTIONS
The authors Allan Vinícius Martins-de-Barros, Fábio Andrey da Costa
Araújo and Marianne de Vasconcelos Carvalho contributed to the
study conception and design; Search strategy, study selection and
data extraction were performed by Allan Vinícius Martins-de-Barros,
Caio César Gonçalves Silva and Marianne de Vasconcelos Carvalho;
critical appraisal of the selected studies was performed by Caio César
Gonçalves Silva and Kalyne Kelly Negromonte Gonçalves; meta-
analysis and additional analysis were performed by Renata de Albu-
querque Cavalcanti Almeida. The first draft of the manuscript was
written by AVMB and EDOS. Manuscript critical review was per-
formed by Fábio Andrey da Costa Araújo, Marianne de Vasconcelos
Carvalho, Liam Robinson and Willie F. P. van Heerden. All authors
commented on previous versions of the manuscript. All authors read
and approved the final manuscript.
ACKNOWLEDGMENTS
We are grateful to the authors who kindly provided data for this
study.
FUND ING INFORMATION
This work was supported by grants from the Research Support Foun-
dation of the State of Pernambuco, Brazil (FACEPE, Fundação de
Amparo a Ciência e Tecnologia do Estado de Pernambuco) and from
the Coordination for the Improvement of Higher Education Person-
nel (CAPES, Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior).
CONF LICT OF IN TE RE ST ST AT E MENT
The authors declare no conflicts of interest.
P EE R R EV I E W
The peer review history for this article is available at https://www.
webofscience.com/api/gateway/wos/peer-review/10.1111/jop.
13458.
DATA AVAI LAB ILITY S TATEMENT
The data that supports the findings of this study are available in the
supplementary material of this article
ORCID
Allan Vinícius Martins-de-Barros https://orcid.org/0000-0002-
5818-1575
16000714, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jop.13458 by UPE - Universidade de Pernambuco, Wiley Online Library on [27/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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SUPPORTING INF ORMATION
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How to cite this article: Martins-de-Barros AV, Silva CCG,
Gonçalves KKN, et al. Does BRAF V600E mutation affect
recurrence rate of ameloblastomas? Systematic review and
meta-analysis. J Oral Pathol Med. 2023;52(8):701‐709. doi:10.
1111/jop.13458