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Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries.

Brown NA, Betz BL - Biomark Cancer (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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).
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f3-bic-suppl.2-2015-019: 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).

Mentions: In addition to BRAF, two studies identified mutations affecting other genes in the MAPK pathway upstream of BRAF (Fig. 2).11,12 The BRAF protein is normally activated by the G-protein RAS. RAS mutations were identified in up to 20% of ameloblastomas, including KRAS, NRAS, and HRAS.12 All RAS mutations occurred at sites commonly mutated in other neoplasms (codons 12 and 61) and are known to lead to constitutive activation of RAS signaling. The 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 that activate MAPK signaling. FGFR2 mutations were identified in 6%–18% of ameloblastomas,11,12 occurring in either the transmembrane (C382R and V395D) or kinase domain (N549K) of the receptor. These 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 present in 78%–88% of ameloblastomas. Importantly, mutations affecting these genes were mutually exclusive in all 65 cases described except one (Fig. 3). This case from Sweeney et al11 demonstrated concomitant mutations of BRAF and FGFR2. The high prevalence and near-complete mutual exclusivity of these mutations suggests that activation of the MAPK pathway likely represents a critical event that occurs early in the pathogenesis of ameloblastoma.


Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries.

Brown NA, Betz BL - Biomark Cancer (2015)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4597444&req=5

f3-bic-suppl.2-2015-019: 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).
Mentions: In addition to BRAF, two studies identified mutations affecting other genes in the MAPK pathway upstream of BRAF (Fig. 2).11,12 The BRAF protein is normally activated by the G-protein RAS. RAS mutations were identified in up to 20% of ameloblastomas, including KRAS, NRAS, and HRAS.12 All RAS mutations occurred at sites commonly mutated in other neoplasms (codons 12 and 61) and are known to lead to constitutive activation of RAS signaling. The 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 that activate MAPK signaling. FGFR2 mutations were identified in 6%–18% of ameloblastomas,11,12 occurring in either the transmembrane (C382R and V395D) or kinase domain (N549K) of the receptor. These 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 present in 78%–88% of ameloblastomas. Importantly, mutations affecting these genes were mutually exclusive in all 65 cases described except one (Fig. 3). This case from Sweeney et al11 demonstrated concomitant mutations of BRAF and FGFR2. The high prevalence and near-complete mutual exclusivity of these mutations suggests that activation of the MAPK pathway likely represents a critical event that occurs early in the pathogenesis of ameloblastoma.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

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.

No MeSH data available.


Related in: MedlinePlus