Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries

Abstract

Ameloblastoma is an odontogenic neoplasm whose molecular pathogenesis has only recently been elucidated. The discovery of recurrent activating mutations in FGFR2, BRAF, and RAS in a large majority of ameloblastomas has implicated dysregulation of MAPK pathway signaling as a critical step in the pathogenesis of this tumor. Some degree of controversy exists regarding the role of mutations affecting the sonic hedgehog (SHH) pathway, specifically Smoothened (SMO), which have been postulated to serve as either an alternative pathogenetic mechanism or secondary mutations. Here, we review recent advances in our understanding of the molecular pathogenesis of ameloblastoma as well as the diagnostic, prognostic, and therapeutic implications of these discoveries.

Full text

19BIOMARKERS IN CANCER 2015:7(S2)
Ameloblastoma: A Review of Recent Molecular
Pathogenetic Discoveries
Supplementary Issue: Signaling Pathways as Biomarkers
Noah A. Brown and Bryan L. Betz
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
ABSTRACT: Ameloblastoma is an odontogenic neoplasm whose molecular pathogenesis has only recently been elucidated. e discovery of recurrent
activating mutations in FGFR2, BRAF, and RAS in a large majority of ameloblastomas has implicated dysregulation of MAPK pathway signaling as a criti-
cal step in the pathogenesis of this tumor. Some degree of controversy exists regarding the role of mutations aecting the sonic hedgehog (SHH) pathway,
specically Smoothened (SMO), which have been postulated to serve as either an alternative pathogenetic mechanism or secondary mutations. Here, we
review recent advances in our understanding of the molecular pathogenesis of ameloblastoma as well as the diagnostic, prognostic, and therapeutic implica-
tions of these discoveries.
KEY WORDS: ameloblastoma, MAPK, BRAF, RAS, odontogenic tumor, therapy
SUPPLEMENT: Signaling Pathways as Biomarkers
CITATION: Brown and Betz. Ameloblastoma: A Review of Recent Molecular Pathogenetic
Discoveries. Biomarkers in Cancer 2015:7(S2) 19–24 doi:10.4137/BIC.S29329.
TYPE: Review
RECEIVED: June 3, 2015. RESUBMITTED: July 13, 2015. ACCEPTED FOR
PUBLICATION: July 14, 2015.
ACADEMIC EDITOR: Barbara Guinn, Editor in Chief
PEER REVIEW: Two peer reviewers contributed to the peer review report. Reviewers’
reports totaled 577 words, excluding any condential comments to the academic editor.
FUNDING: Authors disclose no funding sources.
COMPETING INTERESTS: Authors disclose no potential conicts of interest.
COPYRIGHT: © the authors, publisher and licensee Libertas Academica Limited.
This is an open-access article distributed under the terms of the Creative Commons
CC-BY-NC 3.0 License.
CORRESPONDENCE: bbetz@med.umich.edu
Paper subject to independent expert blind peer review. All editorial decisions made
by independent academic editor. Upon submission manuscript was subject to anti-
plagiarism scanning. Prior to publication all authors have given signed conrmation of
agreement to article publication and compliance with all applicable ethical and legal
requirements, including the accuracy of author and contributor information, disclosure
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relating to human and animal study participants, and compliance with any copyright
requirements of third parties. This journal is a member of the Committee on Publication
Ethics (COPE).
Published by Libertas Academica. Learn more about this journal.
Introduction
Ameloblastoma is an uncommon, locally invasive odontogenic
neoplasm arising in the jaw. e average age of diagnosis is
36 years, with equal incidence in men and women.
1
Most
ameloblastomas (up to 80%) occur in the posterior mandible,
with fewer tumors arising in the maxilla.
1
Patients typically
present with painless swelling of the jaw, and the vast major-
ity of ameloblastomas are slow-growing neoplasms without
metastatic potential. However, ameloblastic tumors with
cytologic atypia are classied as ameloblastic carcinoma and
have a propensity for rapid growth and metastasis.
2
Rarely,
ameloblastic neoplasms metastasize in spite of a benign his-
tologic appearance, and they are classied as metastasizing
ameloblastoma. Current treatment options for ameloblastoma
include both conservative treatment (enucleation or curet-
tage) and resection. e former is associated with high rates of
recurrence, while the latter results in signicant facial defor-
mity and morbidity.
3
Ameloblastoma is thought to arise from cells of the dental
lamina
4
and resembles structures of the cap/bell stage of the
developing tooth.
5
In the 2005 World Health Organization
(WHO) classication, ameloblastomas include four sub-
types based on location and histopathology: solid/multicytic
(91%), unicystic (6%), extra-osseous (2%), and desmoplastic
(1%).
6
Histologically, most tumors display a follicular pat-
tern characterized by islands of epithelium within brous
stroma that lacks inductive capacity to form hard tissue. e
epithelium is comprised of columnar, preameloblast-like,
palisaded cells with reverse polarization at the periphery,
and loosely arranged cells resembling the stellate reticu-
lum in the center (Fig. 1). However, some tumors display a
plexiform pattern of epithelium with inconspicuous stellate
reticulum.
While the molecular pathogenesis of ameloblastoma was
largely unknown prior to 2014, there was mounting evidence
suggesting that activation of the mitogen-activated protein
kinase (MAPK) pathway plays a prominent role. Several
studies demonstrated activation of components of the MAPK
pathway in an ameloblastoma cell line (AM-1) under various
circumstances, including stimulation with tumor necrosis fac-
tor alpha (TNF α)
7
and broblast growth factors 7 and 10.
8
In addition, transgenic mice expressing v-Ha-Ras under the
zeta-globin promoter were shown to develop odontogenic
tumors resembling ameloblastoma.
9
MAPK Pathway Mutations
In 2014, three separate reports identied recurrent MAPK
mutations in ameloblastoma.
10–12
e most common and
rst mutation identied was BRAF V600E. Two of these
reports found BRAF mutations at a similar frequency (64%
and 63%; 54/84 and 15/24),
10,12
while a third demonstrated
a lower frequency (46%; 13/28).
11
A more recent study
reported BRAF mutations in 82% (14/17) of cases.
13
e
combined incidence from all four studies is 62.7% (96/153).
Journal name: Biomarkers in Cancer
Journal type: Review
Yea r: 2015
Volume: 7(S2)
Running head verso: Brown and Betz
Running head recto: Molecular pathogenesis of ameloblastoma

Brown and Betz
20 BIOMARKERS IN CANCER 2015:7(S2)
Figure 1. Histopathology of ameloblastoma. (A) The follicular pattern with islands of odontogenic epithelium within brous stroma. The epithelium
consists of peripheral palisading cells showing reverse polarization and central loosely arranged cells resembling the stellate reticulum. H&E staining
(×100). (B) The plexiform pattern with anastomosing strands of basal cells, delicate stroma, and inconspicuous stellate reticulum. H&E staining (×100).
BRAF is a serine-threonine kinase within the MAPK
pathway. eV600E mutation is present in numerous neo-
plasms including melanoma,
14
hairy cell leukemia,
15
papil-
lary thyroid carcinoma,
16
Langerhans cell histiocytosis,
17
and colorectal cancer.
18
is mutation results in constitutive
activation of the BRAF protein and downstream MEK and
ERK signaling, enhancing cell proliferation, survival, and
ultimately neoplastic transformation.
19
Both Brown et al
12
and Sweeney et al
11
also identied the BRAF V600E muta-
tion in the ameloblastoma cell line AM-1, and demonstrated
evidence of in vitro activation of MAPK signaling that was
blocked by BRAF inhibition.
In addition to BRAF, two studies identied muta-
tions aecting other genes in the MAPK pathway upstream
of BRAF (Fig. 2).
11,12
e BRAF protein is normally acti-
vated by the G-protein RAS. RAS mutations were identied
in up to 20% of ameloblastomas, including KRAS, NRAS,
and HRAS.
12
All RAS mutations occurred at sites com-
monly mutated in other neoplasms (codons 12 and 61) and
are known to lead to constitutive activation of RAS signal-
ing. e activation of RAS and the remainder of the MAPK
pathway is normally triggered by the activation of a growth
factor receptor in response to a growth factor. Fibroblast
growth factor receptor2 (FGFR2) is one of several receptors
Figure 2. Schematic of the mitogen activated protein kinase (MAPK) pathway with mutation frequencies in ameloblastoma based on all studies in which
each gene was evaluated.
10–13

Molecular pathogenesis of ameloblastoma
21BIOMARKERS IN CANCER 2015:7(S2)
that activate MAPK signaling. FGFR2 mutations were iden-
tied in 6%–18% of ameloblastomas,
11,12
occurring in either
the transmembrane (C382R and V395D) or kinase domain
(N549K) of the receptor. ese mutations have been described
in both endometrial carcinoma and craniosynostosis and are
known to result in constitutive MAPK pathway activation
that is abrogated by treatment with FGFR inhibitors.
20–23
Together, FGFR2, RAS, and BRAF mutations are pres-
ent in 78%–88% of ameloblastomas. Importantly, mutations
aecting these genes were mutually exclusive in all 65 cases
described except one (Fig. 3). is case from Sweeney et al
11
demonstrated concomitant mutations of BRAF and FGFR2.
e high prevalence and near-complete mutual exclusivity of
these mutations suggests that activation of the MAPK path-
way likely represents a critical event that occurs early in the
pathogenesis of ameloblastoma.
SMO and Other Mutations
Several mutations were identied within genes not involved
in the MAPK pathway. ese included SMO, CTNNB1,
PIK3CA, and SMARCB1. Of these, SMO mutations were the
most frequent, occurring in 16%–39% of cases.
11,12
SMO muta-
tions included W535L and L412F, which have been previously
described in basal cell carcinoma
24,25
and meningioma,
26,27
as
well as a novel mutation G416E. e Smoothened (SMO) protein
is a nonclassical G-protein-coupled receptor that mediates sonic
hedgehog (SHH) signaling and is normally repressed by patched
(PTCH1) in the absence of the Hedgehog ligand.
28
Polymor-
phisms and deleterious germline mutations within PTCH1 have
been shown to aect the risk of ameloblastoma.
29,30
Sweeney
et al
11
demonstrated increased sonic hedgehog signaling activity
in Smo
-/-
mouse embryonic broblasts carrying SMO L412F.
Furthermore, the eect of this mutation was inhibited by phar-
macologic inhibitors of SHH signaling, including KAAD-
cyclopamine and arsenic trioxide.
It is unclear whether MAPK and the Hedgehog pathway
mutations represent two molecular subclasses of ameloblastoma,
as suggested by Sweeney et al,
11
or whether SMO mutations
function as secondary events with MAPK pathway activation
being the essential driver of pathogenesis, as suggested by Brown
et al.
12
BRAF and SMO were the two most frequently mutated
genes in both studies, and mutations in these genes were mutu-
ally exclusive with one another in all but three instances (16%
of SMO mutated cases). However, SMO mutations frequently
co-occurred with RAS mutations (37% of SMO mutated cases)
and FGFR2 mutations (32% of SMO mutated cases). Sixteen
percent of SMO mutations occurred in the absence of any
MAPK pathway mutations, accounting for 4% of ameloblas-
tomas overall.
Brown et al
12
also identied mutations in several
other genes at a lower frequency. ese included CTNNB1,
PIK3CA, and SMARCB1 present in 4%, 6%, and 6% of cases,
respectively. ese mutations were not mutually exclusive with
one another or with MAPK pathway or SMO mutations. All
mutations have previously been described in other neoplasms.
It is unclear precisely what role these mutations play in the
pathogenesis of ameloblastoma.
MAPK Mutations in Other Odontogenic Tumors
Two studies investigated the pathogenetic specicity of MAPK
pathway mutations, particularly BRAF V600E, by evaluating other
odontogenic tumors. In one study, BRAF mutations were identi-
ed in 2 ameloblastic bromas and 1 ameloblastic brodentinoma
but were not identied in 37 other odontogenic tumors. ese
included ameloblastic carcinoma, odontoameloblastoma, clear cell
odontogenic carcinomas, adenomatoid odontogenic tumor, kera-
tocystic odontogenic tumor, calcifying cystic odontogenic tumor,
calcifying epithelial odontogenic tumor, odontogenic broma,
and odontogenic myxoma.
12
A subsequent study identied
BRAF V600E mutations in 3/8 (38%) ameloblastic carcinomas
and 1/1 clear cell odontogenic tumor, but found no mutations in
either of the two ghost cell odontogenic carcinomas.
13
e pres-
ence of BRAF mutations in ameloblastic carcinoma and amelo-
blastic broma/brodentinoma suggests that these tumors may
be pathogenetically related to ameloblastoma. Some ameloblastic
carcinomas appear to arise from a pre-existing, benign ameloblas-
toma and are therefore designated dedierentiated ameloblastic
carcinoma.
2
While ameloblastic bromas and brodentinomas
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Figure 3. Summary of BRAF, KRAS, HRAS, NRAS, FGFR2, SMO, PIK3CA, CTNNB1, and SMARCB1 mutations in ameloblastoma based on two studies
in which all of these genes were evaluated.
11,12
Colored boxes indicate the presence of mutations in the indicated genes (rows) and samples (columns).
The histologic pattern (plexiform versus non-plexiform) is also indicated (if known).

Brown and Betz
22 BIOMARKERS IN CANCER 2015:7(S2)
tend to occur in younger individuals and exhibit less locally
aggressive behavior, these tumors are histologically very similar
to classic ameloblastoma, diering primarily in the appearance of
the stroma surrounding odontogenic epithelium.
31
Overall, these
ndings suggest that ameloblastic tumors are a distinct group
of odontogenic tumors with characteristic genetic abnormali-
ties. ese ndings also implicate the BRAF V600E mutation
as a potential diagnostic marker in the work-up of odontogenic
tumors that is specic for ameloblastic tumors. Notably, Brown
et al
10
observed perfect concordance between VE1 immunohis-
tochemistry and the molecular detection of BRAF V600E muta-
tions, demonstrating that both techniques may be useful in the
diagnosis of ameloblastic tumors.
Clinicopathologic Associations
e mutation prole of ameloblastomas correlates with
histopathology, location (Fig. 4), age at diagnosis, and prog-
nosis (Fig. 5). As stated earlier, Sweeney et al
11
postulated that
BRAF-mutated and SMO-mutated tumors represent two dis-
tinct molecular subtypes with ameloblastoma with dierent
clinicopathologic features including location, histologic pat-
tern (follicular versus plexiform), and possibly prognosis. e
former two showed statistically signicant associations with
genotype (BRAF-mutated vs SMO-mutated). However, in
the larger series from Brown et al,
12
these associations corre-
lated better with the presence or absence of the BRAF muta-
tion rather than the presence of SMO mutations, which were
found in only a minority of BRAF wild-type tumors (37%).
BRAF mutations were shown to occur much more frequently
in the mandible and only rarely in the maxilla (5.6%), while
43% of BR AF wild-type tumors arose in the maxilla. is
trend was not specic for SMO-mutated tumors; indeed, 64%
of BRAF wild-type, SMO wild-type tumors also arose in the
maxilla.
Sweeney et al
11
observed that 80% of ameloblasto-
mas with the plexiform histologic pattern were BRAF
wild-type, SMO mutant (P , 0.02). Brown et al
10
did not
comment on the relationship of follicular/plexiform pat-
tern and genotype. However, a review of their data shows
that, while there was no statistically signicant association
between plexiform histology and SMO mutations (50% fre-
quency in SMO-mutated compared to 43% frequency in
SMO wild-type), plexiform histology was signicantly more
common among BRAF wild-type tumors (62%) compared
with BRAF-mutated tumors (35%; P , 0.02). Similarly,
when data from these two studies are combined (Fig. 3),
plexiform histology remains signicantly more com-
mon among BRAF wild-type tumors (62% versus 36%;
P = 0.026), while SMO status shows no signicant association.
Brown et al
12
also found that BRAF mutations occurred
in younger patients with a mean age at diagnosis of 34.5years
compared to 53.6 in BRAF wild-type cases (P , 0.0001).
Similarly, the mean age at diagnosis among BRAF wild-type,
SMO wild-type cases was 57.2years. In addition, this study
showed that BRAF V600E is an independent predictor of
recurrence-free survival with BRAF wild-type tumors recur-
ring earlier (P = 0.046). No statistically signicant association
was observed between recurrence and SMO mutation status.
Overall, several clinicopathologic features correlate with
the presence or absence of BRAF mutations and are not spe-
cic for SMO mutations. ese ndings are analogous to
BRAF V600E mutations in melanoma, which also occur in
younger patients and have a dierent anatomic distribution
compared with NRAS and other mutations.
32–35
In mela-
noma, dierent anatomic distributions are thought to result
from dierences in ultraviolet light exposure. It is unclear why
the anatomic distribution diers between BRAF V600E and
BRAF wild-type ameloblastomas.
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Figure 4. Relationship between the anatomic location and mutation frequency in ameloblastoma based on all studies in which BRAF, RAS, FGFR2, and
SMO were evaluated.
10–13,40

Molecular pathogenesis of ameloblastoma
23BIOMARKERS IN CANCER 2015:7(S2)
Implications for erapy
Several small-molecule inhibitors targeting BRAF and MEK
are FDA-approved or in clinical trials for the treatment of neo-
plasms with activating MAPK pathway mutations, principally
BRAF V600E-mutated melanoma. Two separate studies showed
that ameloblastoma cells harboring the BRAF V600E mutation
are sensitive to the BRAF inhibitor vemurafenib invitro.
11,12
More recently, Kaye et al
36
reported a patient with multiply
recurrent ameloblastoma in the mandible and metastatic amelo-
blastoma in the lung that was found to harbor a BRAF V600E
mutation. is patient was treated with a combination of dab-
rafenib (BRAF inhibitor) and trametinib (MEK inhibitor) and
achieved a dramatic response after 8weeks of therapy.
ese ndings suggest a potential role for BRAF and
MEK inhibitors in ameloblastoma treatment. While amelo-
blastoma is typically treated surgically, surgical resection
often results in signicant facial deformity and recurrences
are common. In addition, pharmacological treatment may be
particularly useful in metastatic and locally aggressive cases
and in patients who are poor surgical candidates. A clinical
trial investigating the utility of dabrafenib in BRAF-mutated
melanoma is currently under way.
Other mutations identied in ameloblastoma may also
be targetable. MEK inhibitors are currently being investi-
gated as potential treatment for NRAS-mutated melanoma
and may therefore also be useful in ameloblastomas with RAS
mutations.
37
e utility of FGFR inhibitors is also under
investigation,
38
as is SHH pathway inhibition with medica-
tions such as itraconazole and arsenic trioxide.
39
Conclusion
Great strides have recently been made in our understanding
of the underlying molecular pathogenesis of ameloblastoma.
Mutations aecting several genes within the MAPK pathway
are now known to occur in a large majority of cases. e bio-
logic importance of these mutations is highlighted by their
high frequency and pattern of mutual exclusivity. e BRAF
V600E mutation is the most common mutation, occurring in
approximately two-thirds of cases. e presence or absence
of this mutation correlates with several clinicopathologic
features including location, age at diagnosis, histology, and
prognosis. is mutation has also been shown to be specic
for ameloblastic tumors, suggesting a potential role as a diag-
nostic marker. Somatic mutations aecting the Hedgehog
pathway, specically SMO, are also fairly common. It is cur-
rently unclear whether MAPK and Hedgehog pathway muta-
tions represent two molecular subclasses of ameloblastoma,
or whether SMO mutations function as secondary events
with MAPK pathway mutations being the essential driver
of pathogenesis. However, the higher frequency of MAPK
mutations, the lack of mutual exclusivity of Hedgehog with
MAPK pathway mutations, and the lack of clinicopathologic
associations with SMO that are independent of BRAF status
would argue against viewing SMO-mutated tumors as a truly
distinct subclass of ameloblastoma. Finally, both in vitro and
anecdotal clinical data implicate MAPK pathway inhibition
as a promising future treatment option for ameloblastoma.
Acknowledgment
e authors would like to thank Katherine Betz for her assis-
tance with the artwork.
Author Contributions
Conceived and designed the experiments: NAB, BLB.
Analyzed the data: NAB, BLB. Wrote the rst draft of the
manuscript: NAB, BLB. Contributed to the writing of the
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Figure 5. Clinical and prognostic signicance of the BRAF V600E mutation in ameloblastoma adapted from Brown et al.
12
(A) Box plot showing a
statistically signicant difference in age distribution for BRAF V600E-mutated and BRAF wild-type ameloblastomas (P = 0.0007). Diamond indicates
the mean, middle horizontal line indicates the median, box indicates 25th and 75th percentiles, and whiskers indicate minimum and maximum.
(B) Recurrence-free survival (in years) for BRAF V600E-mutated and BRAF wild-type ameloblastomas using the Kaplan–Meier method.

Brown and Betz
24 BIOMARKERS IN CANCER 2015:7(S2)
manuscript: NAB, BLB. Agree with manuscript results and
conclusions: NAB, BLB. Jointly developed the structure and
arguments for the paper: NAB, BLB. Made critical revi-
sions and approved nal version: NAB, BLB. Both authors
reviewed and approved of the nal manuscript.
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