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Biomolecules 2019, 9(4), 148; https://doi.org/10.3390/biom9040148

Promoter Hypermethylation of Tumor-Suppressor Genes p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers

1
Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka
2
National Cancer Institute of Sri Lanka, Maharagama 10280, Sri Lanka
3
The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD 4059, Australia
4
Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia
*
Author to whom correspondence should be addressed.
Received: 17 March 2019 / Revised: 7 April 2019 / Accepted: 8 April 2019 / Published: 12 April 2019
(This article belongs to the Special Issue Biomarkers for Cancer)
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Abstract

Silencing of tumor-suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis; hence, TSGs may serve as early tumor biomarkers. We determined the promoter methylation levels of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs in salivary DNA from oral cancer (OC) and oropharyngeal cancer (OPC) patients, using methylation-specific PCR coupled with densitometry analysis. We assessed the association between DNA methylation of individual TSGs with OC and OPC risk factors. The performance and the clinical validity of this quadruple-methylation marker panel were evaluated in discriminating OC and OPC patients from healthy controls using the CombiROC web tool. Our study reports that RASSF1A, TIMP3, and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use, and betel quid chewing, indicating the fact that frequent exposure to risk factors may drive oral and oropharyngeal carcinogenesis through TSG promoter hypermethylation. Also, this quadruple-methylation marker panel of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs demonstrated excellent diagnostic accuracy in the early detection of OC at 91.7% sensitivity and 92.3% specificity and of OPC at 99.8% sensitivity and 92.1% specificity from healthy controls. View Full-Text
Keywords: oral cancer; oropharyngeal cancer; tumor-suppressor genes; promoter hypermethylation oral cancer; oropharyngeal cancer; tumor-suppressor genes; promoter hypermethylation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Liyanage, C.; Wathupola, A.; Muraleetharan, S.; Perera, K.; Punyadeera, C.; Udagama, P. Promoter Hypermethylation of Tumor-Suppressor Genes p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers. Biomolecules 2019, 9, 148.

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