The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis
Abstract
:Simple Summary
Abstract
1. Introduction
2. Epigenetics Mechanisms
2.1. DNA Methylation
2.1.1. CpG Islands
2.1.2. DNA Methylases
2.2. Histone Modifications
2.2.1. Histone Acetylation and Deacetylation
2.2.2. Histone Methylation
2.3. Non-Coding RNAs
3. Epigenetic Alterations in Salivary Gland Tumors
3.1. DNA Methylation in Mucoepidermoid Carcinomas (MECs)
3.2. DNA Methylation in Adenoid Cystic Carcinoma (AdCC)
3.3. DNA Methylation in Carcinoma Ex-Pleomorphic Adenoma (Ca Ex-PA)
3.4. DNA Methylation in Acinic Cell Carcinoma
3.5. Non-Coding RNAs Contributing to SGCs
3.6. Tumour to Tumour Interactions
4. Epigenetic Biomarkers for Diagnosis, Prognosis and Treatment Response Prediction of SGCs
5. Epigenetic Drugs in SGC
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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First Author/Year | Country | Gene/Genome Elements | Genome Region | SGC Tumor (Malignant and/or Benign) | Sample Type | Molecular Alteration | Biological Function Associated with Molecular Alteration | References |
---|---|---|---|---|---|---|---|---|
DNA Methylation | ||||||||
Nikolic et al., 2018 | Serbia | p14ARF/p16INK4a | 9p21.3 | Pleomorphic Adenoma/Carcinoma Ex Pleomorphic Adenoma | formalin-fixed, paraffin-embedded (FFPE) samples | hypermethylation | Transcriptional silencing of the p14/ARF gene | [23] |
Wang et al., 2015 | USA | CLIC3 | 9q34.3 | Mucoepidermoid carcinomas (MECs) | FFPE MEC tumor samples | hypermethylation | Oncogenic ole | [24] |
Shieh et al., 2005 | Taiwan | CDH1 | 16q22.1 | Mucoepidermoid carcinomas (MECs) | FFPE MEC tumor samples | hypermethylation | Loss of E-cadherin expression | [25] |
Daa et al., 2008 | Japan | p15, p18, p19, p21, & p27 | 9p21.3, 1p32.3, 19p13.2, 6p21.2, 12p13.1 | Adenoid cystic carcinoma (AdCC) | FFPE AdCC tumor samples | hypermethylation | Cell cycle disruption | [26] |
Williams et al., 2006 | Texas | DAPK, MGMT, RARβ2, anRASSF1 (Ras association domain family protein1 isoform A) | 9q21.33, | Adenoid Cystic Carcinoma, Mucoepidermoid Carcinoma, Acinic cell Carcinoma, Salivary Duct Carcinomas | FFPE tissues from Adenoid cystic carcinoma (AdCC), Mucoepidermoid carcinoma (MECs), Salivary duct carcinoma (SDCs), and acinic cell carcinoma samples | RASSF1 (Ras association domain family protein1 isoform A) and RARβ2 were highly methylated in malignant tumors and MGMT and DAPK in benign neoplasm. | Low or absent protein expression | [27] |
Zhang et al., 2007 | China | E-cadherin | Cadherin 1: 16q22.1 | Adenoid cystic carcinoma (AdCC) | Tissue samples | Hypermethylation | E-cadherin plays a critical role in transducing signals to influence several important biologic processes. Reduced expression of E-cad, caused by genetic and epigenetic events, has been observed in aggressive carcinoma types. promoter methylation of E-cadherin is a more common mechanism for its inactivation. | [28] |
Xia et al., 2017 | China | CDH1 | CDH1 gene located on 16q 22.1 | Salivary carcinoma ex pleomorphic adenoma (CXPA) | Formalin-fixed and paraffin-embedded tissues | Promoter hypermethylation | CDH1 silencing is directly related to advanced tumor stage and an aggressive phenotype. The association of CDH1 methylation with cervical lymph node metastasis, histological grade and advanced tumor stage suggests that the CDH1 gene may be particularly important in salivary CXPA tumor progression. | [29] |
Lee et al., 2008 | Republic of Korea | RARβ2 and RASSF1 | chromosomal region 3p24 and chromosome 3p21.3 | AdCC, adenoid cystic carcinoma, and salivary duct carcinoma. | Tissue samples | Promoter hypermethylation | These genes are tumor suppressor genes and known for their ability to suppress vital cellular processes, including cell-cycle regulation, apoptosis, DNA repair, differentiation, and metastasis. The hypermethylation of the two genes may synergistically involve in the carcinogenesis of these two entities. | [30] |
Li et al., 2005 | Texas | p16INK4a, RASSF1A, and DAPK | chromosome 9p21, chromosome 3p21. 3 and chromosome 9q21.33 | Adenoid cystic carcinoma (AdCC) | Formalin-fixed and paraffin-embedded tissues | Promoter hypermethylation | Promoter methylation of these gene often results in silencing of its expression and is acommon mechanism to inactivate tumor suppressor genes in tumorigenesis. | [31] |
Durr et al., 2010 | United States of America | APC, Mint 1, PGP9.5, RAR-b, andTimp3 | Chromosome 5q22. 2, SPEN gene, chromosome 4p14, chromosome 17q21.2 and Chromosome 22 | Malignant SGTs | Paraffin embedded tissues | Promoter hypermethylation | Promoter methylation of these gene may contribute to salivary gland carcinogenesis | [32] |
Uchida et al., 2004 | Japan | 14-3-3 σ | chromosome 8q22.3 | Adenoid cystic carcinoma (AdCC) | Tissue sample | Hypermethylation | The downregulation of 14-3-3 σ by hypermethylation of the CpG island may contribute to salivary gland carcinogenesis | [33] |
Fan et al., 2010 | China | PTEN | Chromosome 10q23. 31 | Adenoid cystic carcinoma (AdCC) | ACC-2 cell lines | Promoter hypermethylation | The hypermethylation of the PTEN promoter region is one of the major mechanisms leading to reduced expression of PTen in adenoid cystic carcinomas. This indicates that PTen is an important candidate gene involved in the pathogenesis of adenoid cystic carcinomas | [34] |
Maruya et al., 2004 | Japan | E-cadherin | Cadherin 1: 16q22.1 | Adenoid cystic carcinoma (AdCC) | Paraffin-embedded tumor tissues | Hypermethylation | E-cadherin plays a critical role in transducing signals to influence several important biologic processes. Reduced expression of E-cad, caused by genetic and epigenetic events, has been observed in high grade and aggressive tumors. promoter methylation of E-cadherin is a more common mechanism for its inactivation. | [35] |
Kanazawa et al., 2018 | USA | GALR1 and GALR2 | G-protein coupled receptors family | Salivary duct carcinoma (SDC) | Tissue samples | Promoter hypermethylation | The galanin receptors, GALR1 and GALR2, are members of the GPCR superfamily, and serve as important tumor suppressor genes. The silencing of the GALR1 and GALR2 genes by methylation may constitute a critical event in SDC. | [36] |
Tan et al., 2014; Shao et al., 2011 | USA | AQP1 | Aquaporins: located on chromosome 6 in a region with homology of synteny with human 7p14. | Adenoid cystic carcinoma (AdCC) | Tumor tissue sample | Hypomethylation | AQP1 is a small transmembrane protein that selectively transports water across cell membranes. It is highly expressed in several tumor types and has been implicated in tumor cell proliferation, extravasation, migration, and metastasis. AQP1 was significantly hypomethylated in ACC tumors compared with controls | [37,38] |
Ling et al., 2016 | USA | HCN2 | Chromosome 19 | Adenoid cystic carcinoma (AdCC) | Formalin-fixed, paraffin-embedded tissue sample | Promoter hypomethylation | HCN2 normally conducts K+ and Na+, it has been reported that HCN2 was permeable to Ca2+, and it was suggested that they may participate in pathological Ca2+ signaling when HCN2 is overexpressed. Hypomethylation of HCN2 as a potential biomarker for ACC that may be associated with more aggressive disease | [39] |
Ge et al., 2011 | China | RUNX3 gene | Chromosomal region 1p36 | Adenoid cystic carcinoma (AdCC) | Tissue samples | Hypermethylation | The methylation of the promoter 5′-CpG island in the RUNX3 gene is a major gene-silencing mechanism. RUNX3 protein expression is significantly related to metastasis and T stage. | [40] |
HU et al., 2011 | China | P16 | Chromosome 9p21 | Carcinoma ex Pleomorphic adenoma (Ca-ex-PA) | Tissue samples | Promoter hypermethylation | Overexpression of p16 protein in the cytoplasm and decreased expression of p16 protein in the nucleus may play important roles in the evolution of pleomorphic adenoma to Ca-ex-PA | [41] |
Guo et al., 2007 | China | p16INK4a | Chromosome 9p21 | Mucoepidermoid carcinoma (MEC) | Tissue samples | promoter hypermethylation | Alterations of the p16INK4a tumour suppressor gene are often observed in a variety of human cancers and are considered to play a critical role in the transition to malignant growth. the main mechanisms of inactivation of the p16INK4a gene in MEC of the salivary glands are promoter hypermethylation. | [42] |
Sasahira et al., 2011 | Japan | RUNX3 | Chromosomal region 1p36 | Pleomorphic adenoma (PA). Adenoid cystic carcinoma (AdCC) andMucoepidermoid carcinoma (MEC) | Formalin-fixed, paraffin embedded samples | Hypermethylation | RUNX3 inactivation is observed more frequently in salivary gland tumors than in normal salivary gland tissues and RUNX3 downregulation is significantly correlated with tumor progression and poor prognosis in AdCC and MEC | [43] |
Histone modifications | ||||||||
Wanger et al., 2017 | Brazil | H3lys9 | histone H3 at Lys 9 | Adenoid cystic carcinoma, mucoepidermoid carcinomas and acinic cell carcinoma | FFPE tissue blocks of SGTs | Histones are hypoacetylated | histone deposition, chromatin assembly and gene activation | [44] |
Xia et al., 2013 | China | H3K9me3 and H3K9Ac | Trimethylation of histone 3 lysine 9 1q42.13 | Adenoid cystic carcinoma (AdCC) | AdCC tumor samples | Histones were acetylated and methylated | Rapid cell proliferation and distant metastasis in ACC | [45] |
Non-coding RNAs | ||||||||
Binmadi e al., 2018 | Maryland | miR-302a | 4q25 | Mucoepidermoid carcinomas (MECs) | MECs tumor samples | Non-coding RNA was upregulated | Cancer invasions | [46] |
Brown et al., 2019 | Finland | miRNA-150, miRNA-375, and miRNA-455-3p | Chromosome 19q13, chromosome 2 and chromosome 9 at locus 9q32 | Mucoepidermoid carcinomas (MEC) and Adenoid cystic carcinoma (AdCC) | Formalin-fixed paraffin embedded | miRNA-150 and miRNA-375 expression was significantly decreased in AdCC and PAC, whilst miRNA-455-3p showed significantly increased expression in AdCC when compared to PAC. | The post-transcriptional protein expression has been shown to play important roles in neoplastic and non-neoplastic processes. These non-coding RNAs presented alternated expression in SGC. | [47] |
Mitani et al., 2013 | USA | miR-17 and miR-20a | Chromosome 13 | Adenoid cystic carcinoma (AdCC) | Tissue samples | Overexpression of the miR-17 and miR-20a | miRNAs play a role in the regulation of cellular pathways in the ACC tumorigenesis, and this may be influenced by the fusion gene status. Overexpression of the miR-17 and miR-20a were significantly associated with poor outcome in the screening and validation sets | [48] |
Persson et al., 2009 | The Netherlands | miR-15a/16 and miR-150 | Chromosome 13q14 and chromosome 19 | Adenoid cystic carcinoma (AdCC) | Tissue samples | miR-15a/16 was overexpressed in ACC as compared with normal glandular tissues, whereas the expression of miR-150 was lower in ACC than in normal glandular tissues | The deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC. miR-15a/16 and miR-150 recently were shown to regulate MYB expression negatively. The MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC | [49] |
Xu et al., 2019 | China | Different lncRNA and mRNA in PLAG1 gene | Chromosome 8q12 | Carcinoma Ex Pleomorphic Adenoma | Mouse tumors glands | lncRNAs and mRNAs were differentially expressed in PA tissues obtained from PLAG1 transgenic mice as compared with those from control mice. | The differentially expressed mRNAs and lncRNA revealed that these mRNAs were closely associated with a number of processes involved in the development of PA. | [50] |
Flores et al., 2017 | Brazil | miR-15a, miR16, miR-17-5p, miR-21, miR-29, miR-34a and miR-20a | Chromosome 13q14, Chromosome 13q14, chromosome 13, chromosome 17q23.2, chromosome 7q32.3, chromosome 1p36.22 and chromosome 19 | Mucoepidermoid carcinoma (MEC) and Carcinoma Ex Pleomorphic adenoma (PA) | Tissue samples | The expression of miR-21 and miR-34a was upregulated in MEC, respectively. Downregulation of miR-20a was observed in PA and in MEC. The upregulation of miR-15a, miR16, miR-17-5p, miR-21, miR-29, and miR-34a was observed in PA | The expression of apoptosis-regulating miRNAs in salivary gland tumors, suggesting possible involvement of these microRNAs in salivary gland tumorigenesis. | [51] |
Lu et al., 2019 | China | hsa_circ_00123, NON- HSAT154433.1 and circ012342 | circRNA | Mucoepidermoid carcinoma (MEC) | Tissue samples | The circR- NAs showed the highest fold change in MEC group compared with normal control group. The elevated expression of NON- HSAT154433.1 and decreased expression of circ012342 were observed and closely related to the pathogenesis of MEC | An increasing number of circRNAs have been discovered in various diseases and exhibit cell-type or tissue-specific patterns. | [52] |
Lam-Ubol et al., 2022 | Thailand | H3K9Me3 and H3K9Ac | Trimethylation of histone 3 lysine 9 1q42.13 | Mucoepidermoid carcinoma (MEC) and Adenoid cystic carcinoma (AdCC) | Tissue samples | Hyperacetylation and trimethylation of histone H3 | Increased H3 trimethylation at lysine residue 9, as well as H3 acetylation at lysine residue 9 and 18, could be involved in the progression of malignancies. | [53] |
Carcinoma Type | Methylated Genes | References |
---|---|---|
Mucoepidermoid Carcinoma | P14, CLIC3, CDH1, APC, Mint1, PGP9.5, Timp3, p16(INK4A), RUNX3, DAPK, MGMT, RARβ2 and RASSF1 | [3,11,23] |
Adenoid cystic carcinoma | P15, p18, p19, p21, APC, Mint1, PGP9.5, Timp3 Cyclin-dependent kinase inhibitors (p27), HCN2, AQP1, SBSN, RUNX3, DAPK, MGMT, RARβ2 and RASSF1 | [3,26,28,31] |
CA-Ex-PA | RASSF1, p53, p16(INK4A), promoter methylation in CDH1, P14ARF | [29,32,41] |
Acinic cell carcinoma | RASSF1 (Ras association domain family protein1 isoform A) and RARβ2, DAPK, and MGMT | [3] |
Potential Diagnostic Biomarkers | |||||
---|---|---|---|---|---|
Gene/Genome Elements | Genome Region | Sample Type | Molecular Alteration | Tumor Types of SGC (Malignant and/or Benign) | References |
RARβ2 and RASSF1A | Chromosome 3p21. 3 and Chromosome 3p24 | Fresh-frozen tissue specimens | Hypermethylation | Salivary Gland Carcinomas (AdCC, adenoid cystic carcinoma, and salivary duct carcinoma) | [30] |
p16INK4a | Chromosome 9p21 | Tissue samples | Promoter hypermethylation | Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (AdCC) | [31,42] |
p15, p18, p19, p21, and p27 | Chromosome 9p21.3, 1p32.3, 19p13.2, 6p21.2, 12p13.1 | Tissue samples | Promoter hypermethylation | Adenoid cystic carcinoma (AdCC) | [26,94] |
APC, Mint 1, PGP9.5, RAR-b, andTimp3 | Chromosome 5q22. 2, SPEN gene, chromosome 4p14, chromosome 17q21.2 and Chromosome 22 | Tissue samples | Hypermethylation | Malignant SGTs (Pleomorphic adenoma (PA), Mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma AdCC and Salivary duct carcinoma (SDC) | [32] |
14-3-3 σ | chromosome 8q22.3 | Tissue samples | Hypermethylation | Adenoid cystic carcinoma (AdCC) | [33] |
AQP1 | Aquaporins: located on chromosome 6 in a region with homology of synteny with human 7p14. | Tumor tissues | hypomethylation | Adenoid cystic carcinoma (AdCC) | [38] |
SBSN | Suprabasin: 19q13.12 | The saliva of AdCC patients | hypomethylation | Adenoid cystic carcinoma (AdCC) | [38] |
acetyl-H3 (lys9) | histone 3 (H3) acetylation at Lys9 | paraffin-embedded tissue | hypoacetylated | Adenoid cystic carcinoma (AdCC), Mucoepidermoid carcinoma (MEC) and Adenoid cystic carcinoma (AdCC) | [44] |
PTEN | Chromosome 10q23. 31 | ACC-2 cell lines | Promoter hypermethylation | Adenoid cystic carcinoma (AdCC) | [34] |
RASSF1 and RARβ2 | Chromosome 3p24 and chromosome 3p21. 3 | Tissue samples | hypermethylation | Adenoid cystic carcinoma (AdCC) and Salivary duct carcinoma (SDC) | [27] |
E-cadherin | Chromosome 16q22. 1 | Tissue samples | Promoter hypermethylation | Adenoid cystic carcinoma (AdCC) | [35] |
p16INK4a, RASSF1A, and DAPK | chromosome 9p21, chromosome 3p21. 3 and chromosome 9q21.33 | Formalin-fixed and paraffin-embedded tissues | Promoter hypermethylation | Adenoid cystic carcinoma (AdCC) | [31] |
P14, p16, hTERT and TP53 | chromosome 9p21, chromosome 9p21, chromosome 5p15. 33 | formalin-fixed, paraffin-embedded sample | Hypermethylation | Mucoepidermoid carcinoma (MEC) | [23] |
CLIC3 | Chromosome 9 | Tissue samples | Promoter hypomethylation | Mucoepidermoid carcinoma (MEC) | [24] |
HCN2 | Chromosome 19 | Formalin-fixed, paraffin-embedded tissue sample | Promoter hypomethylation | Adenoid cystic carcinoma (AdCC) | [39] |
RUNX3 gene | Chromosomal region 1p36 | Tissue samples | Hypermethylation | Adenoid cystic carcinoma (AdCC) | [40] |
P16 | Chromosome 9p21 | Tissue samples | Promoter Hypermethylation | Carcinoma ex Pleomorphic adenoma(Ca-ex-PA) | [41] |
MiR-455-3p | Chromosome 9 at locus 9q32 | Formalin-fixed paraffin embedded | Significantly increased expression in AdCC | Adenoid cystic carcinoma (AdCC) | [47] |
Different lncRNA and mRNA in PLAG1 gene | Chromosome 8q12 | Mouse tumors glands | lncRNAs and mRNAs were differentially expressed in PA tissues obtained from PLAG1 transgenic mice as compared with those from control mice. | Pleomorphic adenoma (PA) | [50] |
Potential biomarkers of treatment response and prognostic | |||||
Gene/Genome elements | Genome region | Sample type | Molecular alteration | Tumor types of SGC (malignant and/or benign) | References |
EN1 gene | Engrailed Homeobox 1: 2q14.2 | The saliva of AdCC patients | hypermethylation | Adenoid cystic carcinoma (AdCC) | [133] |
SBSN | Suprabasin: 19q13.12 | paraffin-embedded samples | hypomethylation | Adenoid cystic carcinoma (AdCC) | [38] |
AQP1 | Aquaporins: located on chromosome 6 in a region with homology of synteny with human 7p14. | Tumor tissues | hypomethylation | Adenoid cystic carcinoma (AdCC) | [38] |
inactivation of E-cadherin, encoded by CDH1 | Cadherin 1: 16q22.1 | Tissue samples | Promoter hypermethylation | Adenoid cystic carcinoma (AdCC) | [28] |
RASSF1A | Ras Association Domain Family Member 1: 3p21.31 | The saliva of AdCC patients | hypermethylation | Adenoid cystic carcinoma (AdCC) | [134] |
H3k9me3 | 9th lysine residue of the histone H3 protein and is often associated with heterochromatin. | The saliva of AdCC patients | trimethylation of histone 3 lysine 9 | Adenoid cystic carcinoma (AdCC) | [45] |
galanin receptors (GALRs); GALR1 and GALR2 | G-protein coupled receptors family | Tumor specimens | Hypermethylation | Salivary duct carcinoma (SDS) | [36] |
RARβ2 and RASSF1A | Chromosome 3p24 and chromosome 3p21. 3 | Fresh-frozen tissue specimens | Promoter hypermethylation | Malignant Salivary Gland Carcinomas (ACC, adenoid cystic carcinoma, and salivary duct carcinoma) | [30] |
E-cadherin | Cadherin 1: 16q22.1 | Tissue samples | Promoter hypermethylation | Adenoid cystic carcinoma (AdCC) | [35] |
CDH1 | Chromosome 16q22.1 | Formalin-fixed and paraffin-embedded tissues | Promoter hyperrmethylation | Salivary carcinoma ex pleomorphic adenoma (CXPA) | [135] |
RASSF1A | Chromosome 3p21. 3 | Formalin-fixed and paraffin-embedded tissues | Promoter hypermethylation | Adenoid cystic carcinoma (AdCC) | [31] |
14-3-3 σ | Chromosome 8q22.3 | Tissue samples | Hypermethylation | Adenoid cystic carcinoma (AdCC) | [33] |
H3K9Ac, H3K9Me3 and H3K18Ac | Trimethylation of histone 3 lysine 9 1q42.13 and histone H3 lysine 18 | Tissue samples | Hyperacetylation and trimethylation of histone H3 | mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (AdCC) | [136] |
RUNX3 gene | Chromosomal region 1p36 | Tissue samples | Hypermethylation | Adenoid cystic carcinoma (AdCC) and Mucoepidermoid carcinoma (MEC) | [40,43] |
miR-17 and miR-20a | Chromosome 13 | Tissue samples | Overexpression of the miR-17 and miR-20a | Adenoid cystic carcinoma (AdCC) | [48] |
Different lncRNA and mRNAin PLAG1 gene | Chromosome 8q12 | Mouse tumors glands | lncRNAs and mRNAs were differentially expressed in PA tissues obtained from PLAG1 transgenic mice as compared with those from control mice. | Pleomorphic adenoma (PA) | [50] |
hsa_circ_00123 and NON-HSAT154433.1 | circRNA | Tissue samples | The circR-NAs showed the highest fold change in MEC group compared with normal control group. The elevated expression of NON-HSAT154433.1 and decreased expression of circ012342 were observed and closely related to the pathogenesis of MEC | Mucoepidermoid carcinoma (MEC) | [52] |
Agent(s) | Cancer Type(s) | Target | FDA-Approved Date | Trial Details | Trial Identifer/Status | Reference |
---|---|---|---|---|---|---|
Azacytidine (DNMT inhibitor) | HPV-positive HNSCC (resectable disease) | pending | 2014-ongoing (window study) | Recruiting | [137] | |
Decitabine (DNMT unhibitor) | HPV-positive Anogenital and HNSCC (R/M) | Pending | 2019-ongoing (phase 1b) | Recruiting | [138,139] | |
Cabozantinib | All histologies | c-MET | 17 September 2021 | Phase II | Active, not recruiting | [140] |
Nivolumab | All histologies | PD-1 | 4 March 2022 | Phase II | Active, not recruiting | [140,141] |
ivolumab + ipilimumab | All histologies | PD-1 CTLA-4 | 26 May 2020 | Phase II | Active, not recruiting | [142] |
Pembrolizumab | All histologies | PD-1 | 26 July 2021 | Phase II | Recruiting | [142,143] |
Nivolumab + ipilimumab | All histologies | PD-1 CTLA-4 | 26 May 2020 | Phase II | Recruiting | [142] |
Pembrolizumab + lenvatinib | All histologies | PD-1 VEGFR | 10 August 2021 | Phase II | Not yet Recruiting | [142] |
Lutetium-177 PSMA | All histologies | PSMA | 23 March 2022 | Phase II | Not yet Recruiting | [142] |
Axitinib + Avelumab | Adenoid cystic only | VEGFR PD-L1, | 14 March 2019 | Phase II | Recruiting | [142] |
CB-103 | Adenoid cystic carcinoma + other tumors | NOTCH | - | Phase I/II | Recruiting | [142] |
BB1503 (amcarsetinib) | All histologies + other tumors | NOTCH | 5 April 2022 | Phase Ib/II | Active, not recruiting | [142] |
AL101 | Adenoid cystic only | NOTCH | 16 September 2021 | Phase II | Recruiting | [142] |
TeTMYB + BGBA 17 | Solid Tumors | MYB | - | Phase I | Not Yet Recruiting | [142] |
Transtuzumab | Salivary duct carcinoma + other solid tumours | HER2 positive | 2002 | Phase II | Active | [144,145] |
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Mat Lazim, N.; Yousaf, A.; Abusalah, M.A.H.; Sulong, S.; Mohd Ismail, Z.I.; Mohamud, R.; Abu-Harirah, H.A.; AlRamadneh, T.N.; Hassan, R.; Abdullah, B. The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis. Cancers 2023, 15, 2111. https://doi.org/10.3390/cancers15072111
Mat Lazim N, Yousaf A, Abusalah MAH, Sulong S, Mohd Ismail ZI, Mohamud R, Abu-Harirah HA, AlRamadneh TN, Hassan R, Abdullah B. The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis. Cancers. 2023; 15(7):2111. https://doi.org/10.3390/cancers15072111
Chicago/Turabian StyleMat Lazim, Norhafiza, Anam Yousaf, Mai Abdel Haleem Abusalah, Sarina Sulong, Zul Izhar Mohd Ismail, Rohimah Mohamud, Hashem A. Abu-Harirah, Tareq Nayef AlRamadneh, Rosline Hassan, and Baharudin Abdullah. 2023. "The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis" Cancers 15, no. 7: 2111. https://doi.org/10.3390/cancers15072111