Oncology · Medical Literature
Clinical Utility of Molecular Testing in Ameloblastoma: A Systematic Review with Functional Meta-synthesis and Exploratory Meta-analysis.
Abstract
This systematic review with functional meta-synthesis and exploratory meta-analysis evaluated the clinical utility of molecular testing in ameloblastoma, focusing on diagnostic, genotype-phenotype, prognostic, liquid-biopsy, and precision-therapy implications. PubMed/MEDLINE, Scopus, and Embase were searched from inception to April 2026. Eligible studies were full original articles evaluating direct molecular or molecularly interpretable testing in human ameloblastoma. Data were synthesized using functional meta-synthesis. Exploratory random-effects meta-analyses were performed when sufficient study-level data were available. Twenty-nine studies met the inclusion criteria. Molecular testing was most consistently informative for defining the molecular landscape and supporting diagnosis. BRAF V600E was the dominant alteration across the evidence base, but additional alterations in SMO, FGFR2, RAS-family genes, CTNNB1, PIK3CA, EGFR, and ROS1 were reported, particularly in selected or BRAF-wild-type tumors. Exploratory meta-analysis of 19 studies showed a pooled BRAF V600E prevalence of 69.1% (95% CI: 62.1%-75.3%; I2 = 80.3%). Four studies provided complete site-specific data, showing strong enrichment of BRAF V600E in mandibular versus maxillary tumors (OR = 20.13; 95% CI: 7.65-52.95; I2 = 0.0%). BRAF VE1 immunohistochemistry showed high exploratory pooled sensitivity (96.6%; 95% CI: 84.1%-99.4%) and specificity (89.8%; 95% CI: 71.5%-96.8%) when compared with molecular reference methods. Prognostic evidence was inconsistent: BRAF V600E was not a reliable stand-alone recurrence marker, although VEGF mRNA and broader molecular profiles may have prognostic relevance. Plasma cfDNA testing did not reliably detect tissue-positive BRAF V600E. Targeted therapy evidence suggested radiologic response and organ-preservation potential in selected BRAF V600E-mutated tumors, but remained limited to non-randomized series. Molecular testing provides clinically relevant diagnostic and genotype-phenotype information in ameloblastoma and may guide targeted therapy in selected cases. Prognostic and liquid-biopsy applications remain insufficiently validated.
Clinical relevance
Does molecular testing of ameloblastoma provide clinically actionable diagnostic, prognostic, liquid-biopsy, or precision-therapy utility, and what is the pooled prevalence of the BRAF V600E mutation across the published evidence base? __SNAPSHOT__ {"studyDesign":"Systematic review with functional meta-synthesis and exploratory random-effects meta-analysis","setting":"Multi-database literature review (PubMed/MEDLINE, Scopus, Embase); inception to April 2026; no geographic restriction on included primary studies reported in abstract","sampleSize":"29 studies met inclusion criteria; exploratory meta-analysis of BRAF V600E prevalence included 19 studies (total patient-level N not reported in abstract)","population":"Patients with human ameloblastoma evaluated with direct molecular or molecularly interpretable testing in full original articles","intervention":"Molecular testing modalities including mutation profiling (BRAF V600E, SMO, FGFR2, RAS-family genes, CTNNB1, PIK3CA, EGFR, ROS1), liquid biopsy, genotype-phenotype characterization, and precision-therapy evaluation","comparator":"Not applicable (no single comparator arm; studies synthesized via meta-synthesis and exploratory meta-analysis)","primaryOutcome":"Clinical utility of molecular testing across five domains: diagnostic utility, genotype-phenotype correlations, prognostic value, liquid biopsy feasibility, and precision-therapy implications","followUp":"Not reported","fundingSource":"Not reported"}
Key findings
The exploratory random-effects meta-analysis of 19 studies yielded a pooled BRAF V600E prevalence of 69.1% (95% CI: 62.1%–75.3%; I² = 80.3%), indicating high statistical heterogeneity across included studies. BRAF V600E was identified as the dominant molecular alteration across the overall evidence base. Additional alterations were reported in SMO, FGFR2, RAS-family genes, CTNNB1, PIK3CA, EGFR, and ROS1, predominantly in BRAF-wild-type tumors or selected subpopulations. Four studies provided complete site-specific data (further results from this subgroup analysis were not available in the supplied abstract excerpt). No NNT, NNH, absolute risk differences, or response-rate effect sizes for targeted therapies were provided in the available abstract. Prognostic and liquid-biopsy findings were addressed qualitatively via functional meta-synthesis; quantitative effect estimates for these domains were not reported in the abstract. The meta-analysis is characterized by the authors as 'exploratory,' reflecting the heterogeneous nature and limited comparability of included primary studies.
Practice implications
This systematic review establishes that BRAF V600E is the most prevalent molecular alteration in ameloblastoma, with a pooled prevalence of approximately 69%, corroborating prior meta-analyses (pooled estimates of ~70–72% in earlier work). The high I² of 80.3% signals substantial between-study heterogeneity, likely attributable to differences in detection methods (IHC vs. PCR-based sequencing), tumor site, geographic populations, and case selection. Molecular testing was described as most consistently informative for defining the molecular landscape and supporting diagnosis. The clinical utility of liquid biopsy and precision therapy was also evaluated, but the abstract does not report quantitative effect estimates for these domains, precluding conclusions about their magnitude or clinical significance. BRAF-wild-type tumors exhibit a distinct and heterogeneous mutational landscape (SMO, FGFR2, RAS-pathway, CTNNB1, PIK3CA, EGFR, ROS1), underscoring that reflex testing beyond BRAF V600E may be warranted in mutation-negative cases to identify actionable targets. This review does not establish whether molecular subtyping independently alters recurrence rates, surgical decision-making thresholds, or survival outcomes, as these endpoints are not quantitatively reported in the available abstract. Findings apply to patients with histologically confirmed conventional ameloblastoma; generalizability to unicystic, peripheral, or malignant variants is uncertain. This summary is based on the abstract only; full-text data including subgroup analyses, funnel plots, risk-of-bias assessments, and precision-therapy outcome data were not available for review. __LIMITATIONS__ High statistical heterogeneity (I² = 80.3%) in the BRAF V600E pooled prevalence estimate substantially limits the reliability of the point estimate and its direct application to individual clinical settings.,The meta-analysis is explicitly described as 'exploratory,' indicating the authors themselves acknowledge insufficient comparability across studies for definitive inference.,The abstract does not report total patient-level N across all included studies, precluding assessment of overall statistical power.,Detection method heterogeneity (immunohistochemistry vs. various molecular assays) is a well-established source of variance in BRAF V600E prevalence estimates in ameloblastoma and is likely a major driver of between-study heterogeneity.,Liquid-biopsy and precision-therapy domains were apparently addressed by small numbers of studies (four providing site-specific data per the abstract excerpt); patient numbers and effect sizes for these domains are not reported.,The review includes full original articles only; exclusion of abstracts, case series below a specified threshold, or unpublished data introduces potential publication bias.,Funding source is not reported, precluding assessment of industry-related conflicts of interest.,Genotype-phenotype and prognostic conclusions are derived from functional meta-synthesis rather than quantitative meta-analysis, limiting the strength of any causal or prognostic inferences.,Generalizability is limited by the rarity of ameloblastoma (incidence ~0.92/million/year) and by geographic variation in histologic subtype distribution and mutation prevalence.,Only the abstract was available for this summary; full risk-of-bias data, sensitivity analyses, and precision-therapy outcome data could not be assessed. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This systematic review and exploratory meta-analysis confirms BRAF V600E as the dominant oncogenic driver in ameloblastoma, with a pooled prevalence of 69.1% (95% CI: 62.1%–75.3%), though high heterogeneity (I² = 80.3%) limits precise estimation. Routine molecular testing appears justified to support diagnosis and to identify BRAF-wild-type cases harboring alternative actionable targets (SMO, FGFR2, RAS-pathway genes). Precision therapy and liquid-biopsy utility remain investigational; prospective trials with standardized endpoints are needed before these modalities can be integrated into routine clinical management.