| Gene/Alteration | Type of Alteration | Frequency (%) | Clinical Significance | Reference Citations |
|---|---|---:|---|---|
| **CRTC1::MAML2 fusion** | Recurrent gene fusion from t(11;19)(q14-21;p12-13); MAML2 rearrangement | Fusion in up to **80%** of MEC across cohorts; **42%** MAML2 rearrangement in 454-case salivary MEC cohort; detected in **11/27** WTS-profiled MECs in the same cohort | Major oncogenic driver of MEC; diagnostically highly characteristic; present in low-, intermediate-, and high-grade tumors; not consistently associated with better prognosis in contemporary cohorts; cooperates with EGFR/AREG and p16-CDK4/6-RB signaling and is therapeutically targetable in preclinical models (pqac-00000008, pqac-00000001, pqac-00000007) | (pqac-00000008, pqac-00000001, pqac-00000007) |
| **CRTC3::MAML2 fusion** | Alternative MAML2-family fusion | Up to **6%** of MEC; mutually exclusive with CRTC1::MAML2 | Supports MEC diagnosis and indicates biologic overlap with canonical MAML2-rearranged MEC; considered a specific recurrent fusion variant | (pqac-00000008) |
| **MAML2 rearrangement (general)** | Structural rearrangement / fusion event | **50–70%** in prior salivary MEC literature; **42%** in 454-case cohort | Key molecular hallmark used in differential diagnosis by FISH/RT-PCR/NGS; important for classification but not fully prognostic on its own | (pqac-00000001, pqac-00000003, pqac-00000011) |
| **MAML2 mutation / rearrangement** | Mixed category in genomic datasets including rearrangement and substitution | **12%** in WES/WTS-profiled subset of 26 MECs | Reflects recurrent structural and sequence-level alteration of the locus; reinforces central role of MAML2 pathway in MEC biology | (pqac-00000006) |
| **BAP1** | Somatic mutation / DNA damage-response gene alteration | **15%** in 26-case WES subset; **18.6%** in 118 advanced MEC genomic profiling cohort | Most frequently mutated gene in the 454-case genomic study; recurrently altered in aggressive disease datasets, suggesting relevance to tumor evolution and potential DDR-linked vulnerability | (pqac-00000001, pqac-00000006, pqac-00000012) |
| **CDKN2A** | Somatic mutation, deletion, or broader genomic alteration | **8%** mutation in 26-case WES subset; **52.5%** genomic alteration in 118 advanced MECs | Strongly associated with aggressive tumor phenotypes; implicates dysregulated cell-cycle control and supports CDK4/6 pathway as a therapeutic axis | (pqac-00000001, pqac-00000006, pqac-00000002, pqac-00000012, pqac-00000008) |
| **CDKN2B** | Genomic alteration / likely deletion or mutation | **30.5%** in 118 advanced MECs | Frequently co-altered with CDKN2A, further supporting cell-cycle deregulation as a major feature of advanced MEC | (pqac-00000002, pqac-00000012) |
| **TP53** | Somatic mutation / cell-cycle regulatory alteration | **8%** mutation in 26-case WES subset; **40.7%** genomic alteration in 118 advanced MECs | Enriched in aggressive tumor phenotypes; TP53 events superimposed on CRTC1::MAML2 may mark unfavorable prognosis; despite this, many MECs retain wild-type p53, supporting p53-reactivating therapeutic strategies in subsets | (pqac-00000001, pqac-00000006, pqac-00000012, pqac-00000014) |
| **MET** | Somatic mutation | **8%** in 26-case WES subset; **0%** in 118 advanced MEC panel for MET alterations reported there | More frequent in aggressive tumor phenotypes in the 454-case study; potential context-dependent actionable RTK alteration though prevalence varies by cohort/platform | (pqac-00000001, pqac-00000006, pqac-00000012) |
| **PIK3CA** | Somatic mutation / PI3K pathway alteration | **16.9%** in 118 advanced MECs | Common actionable alteration in advanced disease; supports PI3K-AKT-mTOR pathway involvement and potential use of matched targeted therapy | (pqac-00000002, pqac-00000012) |
| **PTEN** | Somatic alteration / tumor suppressor loss | **7.6%** in 118 advanced MECs | Supports activation of PI3K-AKT-mTOR signaling; potentially relevant to pathway-directed therapy | (pqac-00000002, pqac-00000012) |
| **HRAS** | Somatic mutation / RAS pathway alteration | **14.4%** in 118 advanced MECs | Indicates MAPK pathway involvement in a meaningful subset of advanced MEC; potentially targetable indirectly through pathway strategies | (pqac-00000002, pqac-00000012) |
| **KRAS** | Somatic mutation / RAS pathway alteration | **5.1%** overall KRAS alterations; **2.5%** KRAS G12C in 118 advanced MECs | Less common than HRAS but therapeutically relevant because KRAS G12C is a druggable genotype in other cancers | (pqac-00000012) |
| **RB1** | Deletion or genomic alteration | **3.4%** genomic alteration in 118 advanced MECs; focal deletion reported in one metastatic high-grade tumor | Supports disruption of p16-CDK4/6-RB axis, a major cooperating pathway in MEC tumorigenesis | (pqac-00000012, pqac-00000007, pqac-00000008) |
| **CCND1** | Genomic alteration | **3.4%** in 118 advanced MECs | Additional evidence for cell-cycle dysregulation and potential CDK4/6 pathway dependency | (pqac-00000012) |
| **MTAP** | Deletion / genomic alteration | **13.7%** in 118 advanced MECs; deleted with CDKN2A/2B in a recurrent high-grade case | Often co-deleted with CDKN2A/2B; may create therapeutic liabilities linked to methylthioadenosine metabolism / PRMT5-directed strategies in broader oncology | (pqac-00000012, pqac-00000007) |
| **TERT** | Genomic alteration | **15.0%** in 118 advanced MECs | Suggests telomere maintenance pathway involvement in a subset of advanced MEC | (pqac-00000012) |
| **BRCA2** | DNA damage-response alteration | **5.9%** in 118 advanced MECs | May indicate homologous recombination defects in a subset; potentially relevant to PARP-inhibitor sensitivity hypotheses | (pqac-00000012) |
| **ATM** | DNA damage-response alteration | **4.2%** in 118 advanced MECs | Supports occasional DDR pathway disruption | (pqac-00000012) |
| **BRCA1** | DNA damage-response alteration | **1.7%** in 118 advanced MECs | Rare but potentially actionable DDR-related event | (pqac-00000012) |
| **PALB2** | DNA damage-response alteration | **0.8%** in 118 advanced MECs | Rare potential homologous recombination-associated event | (pqac-00000012) |
| **ARID1A** | Chromatin remodeling alteration | **2.5%** in 118 advanced MECs | Suggests chromatin-regulatory disruption in a subset | (pqac-00000012) |
| **FGFR1** | Receptor tyrosine kinase alteration | **5.1%** in 118 advanced MECs | Potentially targetable RTK event in a minority of cases | (pqac-00000012) |
| **ERBB2 (HER2) amplification** | Copy-number gain / amplification | **5.9%** amplification in 118 advanced MECs | Actionable in principle with HER2-directed therapy; one of the clearer targetable alterations in advanced salivary cancers | (pqac-00000002, pqac-00000012, pqac-00000003) |
| **EGFR alteration / AREG-EGFR signaling activation** | Rare genomic alteration; pathway activation by fusion-driven signaling | **0.8%** EGFR genomic alteration in 118 advanced MECs | Even with low alteration frequency, EGFR signaling is biologically important downstream of CRTC1::MAML2; erlotinib showed enhanced preclinical activity when combined with palbociclib | (pqac-00000012, pqac-00000008) |
| **NOTCH1** | Somatic alteration | **4.2%** in 118 advanced MECs | Indicates occasional involvement of NOTCH pathway biology | (pqac-00000012) |
| **NOTCH2** | Somatic alteration | **7.6%** in 118 advanced MECs | Additional evidence for NOTCH pathway perturbation in a subset | (pqac-00000012) |
| **FBXW7** | Somatic mutation | Frequency not stated in cohort summary; identified in fusion-positive poor-prognosis context | Specific FBXW7 events superimposed on CRTC1::MAML2 were associated with unfavorable prognosis in the 454-case study | (pqac-00000001) |
| **EWSR1 rearrangement (general)** | Structural rearrangement / alternative fusion event | **8%** in 454-case cohort | Uncommon but recurrent alternative rearrangement class; important in differential diagnosis and may define molecular subgroups distinct from canonical MAML2-rearranged MEC | (pqac-00000001) |
| **EWSR1::CREM** | Gene fusion | Observed in **1** tumor in 26-case WTS subset | Rare alternative rearrangement detected in MEC; significance still emerging | (pqac-00000007) |
| **EWSR1::ATF1** | Gene fusion | Observed in **1** tumor in 26-case WTS subset | Rare alternative fusion event; may complicate differential diagnosis with other EWSR1-rearranged salivary neoplasms | (pqac-00000007) |
| **SPINK1 (germline)** | Pathogenic germline mutation | **2%** in 26-case WES subset | Cancer-susceptibility finding reported in a small subset; clinical significance for MEC predisposition remains uncertain | (pqac-00000006) |
| **FANCG (germline)** | Pathogenic germline mutation | **2%** in 26-case WES subset | Germline cancer-susceptibility finding of uncertain MEC-specific contribution | (pqac-00000006) |
| **Copy-number amplifications (global)** | CNV amplification burden | **437** amplifications across **26** profiled tumors | Demonstrates substantial structural genomic complexity in a subset of MECs, particularly advanced/high-grade disease | (pqac-00000007) |
| **Copy-number deletions (global)** | CNV deletion burden | **11** deletions across **26** profiled tumors | Deletions include key tumor suppressor and cell-cycle genes, supporting progression biology | (pqac-00000007) |
| **CYSLTR2 / ITM2B / RCBTB2 / RB1 deletions** | Focal deletions in one tumor | Single high-grade metastatic case | Associated with brain-metastatic high-grade MEC in the 26-case genomic subset; may mark aggressive progression biology | (pqac-00000007) |
| **EMT-related transcriptomic program** | Gene-expression / pathway activation rather than discrete mutation | Not expressed as %; enriched in MEC transcriptomic profiling | High EMT scores correlated with poor prognosis and immune activation; highlights molecular heterogeneity beyond DNA alterations | (pqac-00000013) |
| **SLC2A1-AS1 and CERS6-AS1** | lncRNA dysregulation | Not expressed as % | Proposed mediators of EMT and tumor immune microenvironment in MEC; candidate biomarkers/targets from recent transcriptomic analysis | (pqac-00000013) |


*Table: This table summarizes the major recurrent genomic and molecular alterations reported in mucoepidermoid carcinoma, including fusion events, somatic mutations, CNVs, and transcriptomic features. It is useful for linking diagnostic markers and biologic drivers to prognosis and potential targeted therapy strategies.*