Working Paper Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 17 March 2019 / Approved: 19 March 2019 / Online: 19 March 2019 (12:56:24 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Biomolecules 2019, 9, 148
DOI: 10.3390/biom9040148

Abstract

Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an earlyevent in carcinogenesis; Hence TSGs may serve as early tumor biomarkers. We determinedthe 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. We evaluated the performance and the clinical validity of this quadruple methylation marker panel in discriminating OC and OPC patients from healthy controls using CombiROC web tool. Our study reported that RASSF1A, TIMP3 and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. We found that DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use and betel quid chewing by indicating that 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 OPC at 99.8% sensitivity and 92.1% specificity, from healthy controls.

Subject Areas

Oral cancer; Oropharyngeal cancer; Tumor-suppressor genes; Promoter hypermethylation

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