Table 1. Important Genetic Alterations in Salivary Gland Cancers.
| Cancer Type/Genetic Alteration | Gene(s) | Role in Tumor Pathogenesis |
|---|---|---|
| Mucoepidermoid carcinoma (MEC) Translocation, fusion transcript | MECT1-MAML2 (O'Neill 200913) | Activate the Notch target gene Hes-1 in the absence of Notch ligand (Kaye 200619); activate CREB inducible genes that regulate cell proliferation and differentiation (O'Neill 2009,13 Kaye 200619) Exact function unknown |
| Copy number variation | CRTC3-MAML2 (Nakayama 200928) HER2, EGFR (Ettl 201224) | Growth factor receptors, overexpression associated with poor rates of metastases and survival (Ettl 201224) |
| DCC, SMAD4 (Jee 201326) | Various tumor suppressor genes, exact role in MEC unknown (Jee 201326) | |
| Epigenetic | LYN, MOS, PLAG6 (Jee 201326) CDKN2A/p16 (Anzick 201027) | Various oncogenes, exact role in MEC unknown (Jee 201326) Tumor suppressor gene, cell cycle regulator, deletion/hypermethylation associated with poor survival (Anzick 201027) |
| Adenoid cystic carcinoma (ACC) Translocation, fusion transcript | MYB-NFIB (Persson 200937) | MYB is an oncogene involved in cell proliferation, apoptosis, and differentiation; downstream targets include c-kit, cox-2, and bcl2 (Bell 201140); controversial association with patient survival (Mitani 2011,41 Rettig 201543) |
| Epigenetic changes | APC, Mint1, PGP9, RAR-β, Timp3 (Durr 201058) p27 (Daa 200859) | Various tumor suppressor genes, hypermethylated in ACC, exact role unknown (Durr 201058) Cell cycle regulator hypermethylated in ACC, leads to down-regulation and disruption of cell cycle (Daa 200859), role in prognosis unknown |
| EN1 (Liu 201260) | Homeobox gene hypermethylated in ACC, correlates with histologic tumor grade and patient survival (Liu 201260) | |
| AQ1 (Shao 2011,61 Tan 201462) | Transmembrane protein for water transport, hypomethylated in ACC, hypermethylation is associated with better survival (Shao 2011,61 Tan 201462) | |
| SBSN (Shao 201263) | Involved in epidermal differentiation, anchorage-independent growth, hypomethylated in ACC and associated with increased risk of recurrence (Shao 201263) | |
| Copy number losses/deletion | 12q12-q13, 1p32-36, and gains at 22q12-q13, 8, 16p, 17q, 18 (Liu 201260) | High presence of tumor suppressor genes at these loci, exact role in ACC unknown (Liu 201260) |
| Hotspot 6q24.1-q25.1 including PLAG1, LATS1 (Rutherford 200668) | Tumor suppressor genes, exact role in ACC unknown (Rutherford 200668) | |
| Copy number gains/up-regulation | c-kit (Holst 1999,48 Freier 200549) | Transmembrane tyrosine kinase receptor, overexpression associated with worse tumor grade (Holst 1999,48 Freier 200549) |
| EGFR (Monteiro 200957) | Growth factor receptor, overexpression associated with worse histologic grade (Monteiro 200957) | |
| Salivary duct carcinoma (SDC) Aneuploidy/up-regulation | HER2 (Zhu 20156) | Growth factor receptor, overexpression in SDC associated with worse recurrence rates, metastases, and survival (Zhu 20156) |
| p53 (Zhu 20156) | Plays a role in genome stability, overexpression in SDC associated with worse recurrence rates, metastases, and survival (Zhu 20156) | |
| AR (Simpson 201470) | Androgen receptor (AR)-negative tumors are more aggressive than AR-positive tumors (Simpson 201470) | |
| Mammary analogue secretory carcinoma (MASC) Translocation | ETV6-NTRK3 (Stenman 201471) | Fusion product is a chimeric tyrosine kinase with the ability to activate the Ras-MAP pathway and PI3K-Akt pathway (Stenman 201471), role in prognosis unknown |
| Hyalinizing clear cell carcinoma (HCCC) Translocation | EWSR1-ATF (Stenman 201372) | Exact function unknown (Stenman 201372) |
| Carcinoma ex pleomorphic adenoma Rearrangements | PLAG1, HMGA2 | Transcription factors that can undergo a variety of rearrangements; consequences of rearrangements unknown (Stenman 201372) |
Abbreviations: Akt, protein kinase B; APC, adenomatosis polyposis coli; AQ1, aquaporin 1; ATF, activating transcription factor; bcl2, B-cell chronic lymphocytic lymphoma/leukemia 2; CDKN2A/p16, cyclin-dependent kinase inhibitor 2A; c-kit, mast/stem cell growth factor receptor (proto-oncogene c-Kit or tyrosine protein kinase Kit); cox-2, cytochrome c oxidase subunit II; CREB, cyclic AMP responsive binding protein; CRTC3, CREB regulated transcription coactivator 3; DCC, deleted in colorectal carcinoma; EGFR, epidermal growth factor receptor; EN1, engrailed homeobox 1; ETV6, ets variant 6; EWSR1, Ewing sarcoma RNA binding protein 1; HER2, human epidermal growth factor receptor 2; Hes-1, hes family basic helix-loop-helix transcription factor 1; HMGA2, high-mobility group AT-hook 2; LATS1, large tumor suppressor kinase 1; LYN, LYN proto-oncogene, Src family tyrosine kinase; MAP, mitogen-activated protein; MAML2, mastermind-like transcriptional coactivator 2; MECT1, mucoepidermoid carcinoma translocated-1; Mint1, amyloid β precursor protein-binding family A, member 1 (APBA1) adaptor protein; MOS, v-mos Moloney murine sarcoma viral oncogene homolog; MYB, v-myb avian myeloblastosis viral oncogene homolog; NFIB, nuclear factor I/B; NTRK3, neurotrophic tyrosine kinase, receptor, type 3; p16, CDKN2A multiple tumor suppressor; p27, cyclin-dependent kinase inhibitor 1B; p53, tumor protein 53; PGP9, P-glycoprotein 9; PI3K, phosphoinositide 3-kinase; PLAG1, pleomorphic adenoma 1; PLAG4, pleomorphic adenoma 4; RAR-β, retinoic acid receptor β; Ras, rat sarcoma; SBSN, suprabasin; SMAD4, SMAD family member 4; Timp3, TIMP metallopeptidase inhibitor 3.