p16^INK4A and p14^ARF Gene Promoter Hypermethylation as Prognostic Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma: A Review

Table 1

Candidate genes frequently silenced by promoter hypermethylation in OSCC tumor tissue.

Mechanism	Gene	Gene function	Clinicopathological association^a	References
Cell cycle regulation	CYCA1	Cell cycle	Lower histological grade	[37, 47]
	CHFR	Early G2/M checkpoint	Higher T status	[48, 49]
	p14^ARF	Proapoptosis	LNM^b, T status (T2-3), advanced stage; Reduced recurrence rate, favourable prognosis	[32, 40–42, 50, 51]
	p15	Cyclin-dependent kinase inhibitor 2B	Anatomic site (tongue SCC); Alcohol and tobacco use	[35, 41, 50]
	p16^INK4A	Regulates cell cycle G1 progression	Larger tumor size, LNM, advanced stage; Younger age, increased recurrence rate, poor prognosis	[29, 30, 32–35, 37, 40–42, 50, 52–54]
DNA repair	hMSH1/hMSH2	DNA mismatch repair	—	[35, 38, 55]
	MGMT	Guanine alkylation repair	Reduced overall survival; Reduced disease-free survival	[29, 35, 38, 56]
Signal transduction	EDNRB	Endothelin receptor type B	Alcohol and tobacco use	[30, 34]
	RUNX3	Wnt pathway antagonist	LNM, advanced stage, poor differentiation	[34, 38, 57, 58]
	SFRP1	Wnt pathway antagonist	Male gender	[59]
Tissue invasion/metastasis	ECAD	Calcium-dependent cell-cell adhesion; glycoprotein	LNM, increased metastatic potential; Reduced disease-free survival	[35, 60–62]
Tumor suppression	HIN1	Inhibitor Ras pathway	Reduced disease-free survival	[63]
	DAPK1	Proapoptosis	LNM	[38, 41]
	DCC	Proapoptosis	Invasion of bone and deep tongue; Reduced survival	[30, 41]
	RASSF1A/RASSF2	Negative RAS effector, proapoptotic, microtubule stabilization	Decreased disease-free survival; radioresistance	[38, 63]
Other	KIF1A	Cell division and microtubule-dependent intracellular organelle transport	Malignant histology	[30, 64]

aReported significant associations and trends.
^bLymph node metastasis.