p16^INK4Aand p14^ARFGene Promoter Hypermethylation as Prognostic Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma: A Review

Abstract

Head and neck squamous cell carcinoma is a heterogeneous group of tumors with each subtype having a distinct histopathological and molecular profile. Most tumors share, to some extent, the same multistep carcinogenic pathways, which include a wide variety of genetic and epigenetic changes. Epigenetic alterations represent all changes in gene expression patterns that do not alter the actual DNA sequence. Recently, it has become clear that silencing of cancer related genes is not exclusively a result of genetic changes such as mutations or deletions, but it can also be regulated on epigenetic level, mostly by means of gene promoter hypermethylation. Results from recent studies have demonstrated that DNA methylation patterns contain tumor-type-specific signatures, which could serve as biomarkers for clinical outcome in the near future. The topic of this review discusses gene promoter hypermethylation in oral and oropharyngeal squamous cell carcinoma (OSCC). The main objective is to analyse the available data on gene promoter hypermethylation of the cell cycle regulatory proteins p16INK4A and p14ARF and to investigate their clinical significance as novel biomarkers in OSCC. Hypermethylation of both genes seems to possess predictive properties for several clinicopathological outcomes. We conclude that the methylation status of p16INK4A is definitely a promising candidate biomarker for predicting clinical outcome of OSCC, especially for recurrence-free survival.

p16 expression independent of human papillomavirus is associated with lower stage and longer disease-free survival in oral cavity squamous cell carcinoma

“…Similar findings have also been reported by Chung et al 21 and Lingen et al 13 Integration of HPV oncoproteins, E6 and E7, leads to degradation of tumour suppressors p53 and Rb. 7,22 The loss of Rb leads to the increased expression of p16 INK4A protein, encoded by the tumour suppressor gene, CDKN2A, 23 that can be readily detected using immunohistochemistry 23,24 and is considered a surrogate marker for HPV infection in the oropharynx, uterine cervix, and the anal canal. 3 However, other chromosomal alterations in cell cycle regulators such as p53 and p14 pathways, 23,25 transforming growth factor-b II receptor, 26 CDK4 27 and the epidermal growth factor receptor (EGFR) 28 can cause p16 overexpression independent of HPV as observed in this study.…”

“…Al-Kaabi et al postulate that p16 expression prevents cellular proliferation by preventing the progression from the G1 to the S phase in the cell cycle. 23 p16 has also been shown to play an important role in mediating senescence leading to cell death in the setting of genetic damage which may initiate or potentiate neoplasia. 30 Dong et al 31 observed that homozygous p16 deletion was significantly more frequent in pT3 and pT4 tumours as compared to pT1 and pT2 tumours in their cohort of 30 cases of buccal SCC.…”

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

“…Using its SRA domain, UHRF1 interacts with histone deacetylase 1 (HDAC1) and DNMT1 [7, 31, 33]. This interaction takes place at methylated promoter regions of several TSGs including p16 INK4A , p14 ARF (known as p19 ARF in mouse), both encoded by the CDKN2A gene [34], and RARalpha [7]. However, to our knowledge no data are so far available in the literature about the consequence on p14 ARF and RAR protein levels [7].…”

Epigenetic Biomarkers in Personalized Medicine

“…Aberrant methylation in NELL1, TAC1, and FHIT was associated with poor prognosis, and TLSC1 methylation was associated with aggressive tumor IV. CDKN2A (p16) is a promising candidate biomarker for predicting clinical outcome of oropharyngeal squamous cell carcinoma, especially for recurrence-free survival [147]. Patients with high UCHL1 methylation levels had poorer 5-year survival rates and also an increased incidence of lymph nodes metastases versus those with lower methylation values.…”