| |
|
|
| Year : 2014 | Volume
: 25
| Issue : 6 | Page : 797-805 |
|
| Promoter hypermethylation patterns of P16, DAPK and MGMT in Oral Squamous Cell Carcinoma: A systematic review and meta-analysis |
|
|
KR Don1, Pratibha Ramani1, Vijayalakshmi Ramshankar2, Herald Justin Sherlin1, Priya Premkumar1, Anuja Natesan1
1 Department of Oral and Maxillofacial Pathology, Saveetha Dental College, Chennai, Tamil Nadu, India
2 Department of Preventive Oncology, Research Division, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India
Click here for correspondence address and email
| Date of Submission | 16-Jul-2014 |
| Date of Decision | 14-Aug-2014 |
| Date of Acceptance | 15-Jan-2015 |
| Date of Web Publication | 02-Mar-2015 |
|
|
 |
|
 Abstract | | |
Background: Oral squamous cell carcinoma (OSCC) is a common cancer world-wide that is highly lethal due to its recurrence and metastasis. Methylation is a common epigenetic mechanism that leads to gene silencing in tumors and could be a useful biomarker in OSCC. The prevalence of P16, death-associated protein kinase (DAPK) and O 6 -methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation in OSCC has been evaluated for several years while the results remain controversial.
Objective: The aim of this systematic review is to critically analyze and perform a meta-analysis on the various studies in the literature that have reported the promoter hypermethylation of P16, DAPK and MGMT genes in OSCC.
Search Strategy: Articles were searched and selected through PubMed. Hand search from the relevant journals was also performed. Articles were reviewed and analyzed.
Results: The estimated prevalence of P16 methylation was 43%, DAPK methylation was 39.7% and MGMT methylation was 39.8%. Heterogeneity in methylation prevalences and correlations with the clinical outcomes of the disease prevailed in various studies.
Conclusion: We can conclude from our systematic review that a higher prevalence of methylation of P16, DAPK and MGMT occur in OSCC. Further studies are required to substantiate the role of methylation of P16, DAPK and MGMT as a marker in OSCC. Keywords: Death-associated protein kinase, O 6 -methylguanine-DNA-methyltransferase, oral squamous cell carcinoma, P16, promoter hypermethylation
How to cite this article:
Don K R, Ramani P, Ramshankar V, Sherlin HJ, Premkumar P, Natesan A. Promoter hypermethylation patterns of P16, DAPK and MGMT in Oral Squamous Cell Carcinoma: A systematic review and meta-analysis. Indian J Dent Res 2014;25:797-805 |
How to cite this URL:
Don K R, Ramani P, Ramshankar V, Sherlin HJ, Premkumar P, Natesan A. Promoter hypermethylation patterns of P16, DAPK and MGMT in Oral Squamous Cell Carcinoma: A systematic review and meta-analysis. Indian J Dent Res [serial online] 2014 [cited 2023 Sep 26];25:797-805. Available from: https://www.ijdr.in/text.asp?2014/25/6/797/152208 |
The term "oral cancer" refers to malignancy arising from oral tissues. Carcinoma is the term for a malignant tumor of epithelial origin. Oral cancer is the most frequent cancer of the head and neck region, with squamous cell carcinoma being by far the most common single entity, accounting alone for about 90-95% of all malignancies of the oral cavity.
Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy in the world. Approximately, 405,000 cases of OSCC are diagnosed each year, with a rising incidence in many countries. [1] Due to its relative high mortality and low cure rate, OSCC represents a major public health problem. The WHO acknowledged that the 5 years survival rate of these patients has not improved over the past few decades despite treatment advances. [2],[3] Early detection of OSCC is important to reduce mortality rates and to help provide successful cancer treatment.
The etiology of OSCC is multifactorial and involves intrinsic and extrinsic factors. The major risk factors include tobacco and alcohol intake, as well as human papillomavirus infection. [4],[5] These predisposing factors may lead to a wide range of genetic and epigenetic events that promote genomic instability and tumor development and progression.
The genetic alterations involved in the development and progression of OSCC are caused by irreversible changes in DNA sequence including gene deletions, amplifications and mutations leading both to oncogenes activation or tumor-suppressor genes inactivation. [6],[7]
Epigenetics is another major event in the development and progression of OSCC. The epigenetic changes refer to any reversible heritable modifications in gene expression without alterations of the DNA sequence. They occur more frequently than gene mutations. [8]
Methylation is a common epigenetic mechanism that leads to gene silencing in tumors and could be a useful biomarker in OSCC. DNA methylation refers to the covalent addition of a methyl group which usually takes place at the 5' position of the cytosine residues of CpG nucleotides. The CpG dinucleotides are found in 1/80 dinucleotides in 98% of the human genome. They are usually present in regions called CpG islands, which are usually located at promoter regions of the gene. [9] CpG islands have >55% GC content and span > 500 bp. Methylation serves to decrease expression of a gene. CpG islands are often found hypermethylated in tumors, causing the transcriptional "silencing" of tumor-suppressor genes, contributing to cancer progression. On the contrary, it also serves as a mechanism of oncogene activation by hypo/demethylation.
The enzymes directly responsible for CpG island hypermethylation of tumor-suppressor genes are known as DNA-methyltransferases. The methylated-cytosine-guanine sequences are recognized by methyl-cytosine binding proteins, which in turn help in binding of histone deacetylase enzyme. This results in the removal of acetyl groups from histone. This leads to aggregation of nucleosomes to form the heterochromatin, which results in transcriptional silencing of gene.
The genes found hypermethylated in OSCC cover a wide range of cellular processes, including cell cycle control (P16, P15, P14), apoptosis (death-associated protein kinase [DAPK], RASSF1A), Wnt signaling (APC, WIF1), cell-cell adhesion (E-cadherin), and DNA-repair (O 6 -methylgua nine-DNA-methyltransferase [MGMT], hMLH1). [10]
In this review, we assessed the promoter region hypermethylation of P16, MGMT, and DAPK in OSCC.
The cyclin-dependent kinase inhibitor (CDKI) p16 belongs to INK4 family and is involved in cell cycle control. INK4 family of CDKIs include p16 (CDKN2A), p15 (CDKN2B), p18 (CDKN2C), and p19 (CDKN2D). INK4 family has selective effects on cyclin D/CDK4 and cyclin D/CDK6. P16 (INK4a) binds to cyclin D-CDK4 and thereby inhibits CDK4 and promotes the inhibitory effects of retinoblastoma protein (RB) by preventing phosphorylation of RB. CDKN2A gene maps on chromosome 9p21.3 and induces cell cycle arrest in the G1 phase.
O 6 -methylguanine-DNA-methyltransferase gene is located on chromosome 10q26, which encodes MGMT, a DNA-repair enzyme that removes O 6 -guanine-DNA adducts caused by alkylating agents. CpG island hypermethylation of the MGMT promoter region results in gene silencing with loss of MGMT repair capacity which is thought to drive cancer progression. Epigenetic silencing of MGMT has been associated with OSCCs where tobacco exposure and betel quid chewing are suspected to be etiological factors. [11] Elevated MGMT expression has been associated with resistance to alkylating chemotherapeutic agents. [12]
Death-associated protein kinase 1 gene maps on chromosome 9q34.1. DAPK encodes a pro-apoptotic calcium/calmodulin regulated serine/threonine kinase that is required for apoptosis induced by interferon-gamma (IFN-g). [13] Loss of its expression via promoter hypermethylation has been associated with the formation of metastases and advanced disease stages in multiple cancer types, including head and neck cancers. [14] Regarding OSCCs, DAPK hypermethylation has been reported as associated with an increased likelihood of lymph node involvement.
| Methods | |  |
0Search strategy for identification of studies
The search strategy was in accordance with the Cochrane guidelines for systematic reviews. Articles relevant to the search strategy were identified from search databases of PubMed, Medline till the year 2013. Due to the scarcity of methylation pattern studies in OSCC, we wished to exhaust all the possible articles; therefore, a timeline was not included in the search. The article search included only those published in the English literature. The internet search was also done to obtain the relevant articles of our interest. The title of the articles and abstracts was reviewed. The full text of selected articles were retrieved and further analyzed.
Search methodology
The search methodology applied in PubMed was using the following keywords:
Search ((((((((hypermethylation) OR DNA hypermethylation) OR CpG island hypermethylation) OR promoter hypermethylation)) AND ((((((((((P16) OR P16 gene) OR P16 INK4a) OR P16 expression) OR inhibitory kinase4A) OR CDKN2A) OR cyclin CDKI2A) OR INK4A) OR MTS1) OR multiple tumor-suppressor 1)) OR ((((((DAPK) OR DAPK1) OR DAPK gene) OR DAPK expression) OR DAPK) OR DAPK gene)) OR (((((MGMT) OR MGMT gene) OR MGMT expression) OR MGMT) OR MGMT gene)) AND (((((((((oral cancer) OR oral carcinoma) OR oral squamous cancer) OR oral squamous carcinoma) OR oral squamous cell cancer) OR OSCC) OR squamous cell carcinoma of oral cavity) OR SCC of oral cavity) OR OSCC).
In addition, the internet search was also done using the key words "promoter hypermethylation" and "P16 DAPK and MGMT" and "OSCC." Articles in which patients had confirmed with a diagnosis of OSCC with or without the control group regardless of the stage of the tumor were considered for this review.
Selection of studies
Inclusion criteria
- Studies that evaluated the promoter hypermethylation patterns of P16, DAPK and MGMT genes in OSCC
- Studies in which P16, DAPK and MGMT methylation status was examined using methylation-specific PCR (MSP) or quantitative MSP or restriction-multiplex PCR or nested PCR
- Studies in which the specimens used for methylation analysis include fresh cancer tissues samples or formalin fixed paraffin-embedded tissues
- Studies in which the same patient population reported in several publications, only the most recent report or the most complete one with more number of sample size was included in this analysis in order to avoid overlapping between cohorts
- Studies that have undertaken a minimal of 20 samples of OSCC patients
- Studies in English language were included.
Exclusion criteria
- Studies in which methylations examined in the cell lines were excluded
- Studies conducted on animal models were excluded
- Studies conducted on patients who were under radiotherapy and chemotherapy was excluded.
Methods of review
The selection and exclusion of the reviewed studies are summarized in [Figure 1]. The search strategy identified 16 studies that evaluated the promoter hypermethylation of P16, DAPK and MGMT genes in OSCC. The description of the individual studies is shown in [Table 1] and that of the excluded studies in [Table 2]. | Figure 1: Flow chart showing selection and exclusion of the reviewed studies
Click here to view |
Data extraction
Once the articles to be reviewed were finalized, data were extracted from each article, tabulated and was verified and interpreted, and a meta-analysis was performed.
Outcomes
The outcomes assessed in this review examined and analyzed the promoter hypermethylation patterns of P16, DAPK and MGMT genes in OSCC.
| Results | | |
0Included studies
Out of the 16 included studies, the frequencies of promoter hypermethylation of P16 gene in OSCC were evaluated in 15 studies, the frequencies of promoter hypermethylation of DAPK gene in OSCC were evaluated in five studies and the frequencies of promoter hypermethylation of MGMT gene in OSCC were evaluated in eight studies. So, three separate meta-analysis was performed to assess the methylation status of P16, DAPK and MGMT genes in OSCC. The description of the individual studies included for each meta-analysis is shown in [Table 3] [Table 4] [Table 5] respectively. The data of the studies were analyzed to check for heterogeneity and publication bias.
Outcomes
Our meta-analysis data of P16 methylation status showed that the overall estimated pooled prevalence of P16 methylation among 932 OSCC cases in 15 studies was 43% (confidence interval [CI] = 40-46%). Heterogeneity of results among studies prevailed [Figure 2] and [Figure 5]. | Figure 2: Chart depicting the frequency of P16 methylation found by different authors
Click here to view |
The funnel plot analysis for prevalence of P16 methylation in OSCC cases showed heterogeneity. Only 6 studies out of 15 fall within the funnel clearly indicating publication bias [Figure 6].
Our meta-analysis data of DAPK methylation status showed that the overall estimated pooled prevalence of DAPK methylation among 330 OSCC cases in five studies was 39.7% (CI = 15.0-64.3%). Heterogeneity of results among studies prevailed [Figure 3] and [Figure 7]. | Figure 3: Chart depicting the frequency of death-associated protein kinase methylation found by different authors
Click here to view |
The funnel plot analysis for prevalence of DAPK methylation in OSCC cases showed heterogeneity. None of the studies fall inside the funnel clearly indicating publication bias [Figure 8].
Our meta-analysis data of MGMT methylation status showed that the overall estimated pooled prevalence of MGMT methylation among 509 OSCC cases in eight studies was 39.8% (CI = 25.2-54.3%). Heterogeneity of results among studies prevailed [Figure 4] and [Figure 9].  | Figure 4: Chart depicting the frequency of O6-methylguanine-DNAmethyltransferase methylation found by different authors
Click here to view |
The funnel plot analysis for prevalence of MGMT methylation in OSCC cases showed heterogeneity. Five studies out of eight fall inside the funnel indicating little publication bias [Figure 10]. | Figure 5: Forrest plot of P16 promoter methylation in oral squamous cell carcinoma
Click here to view |
 | Figure 7: Forrest plot of DAPK promoter methylation in oral squamous cell carcinoma
Click here to view |
 | Figure 8: Funnel plot of studies with death-associated protein kinase promoter methylation
Click here to view |
 | Figure 9: Forrest plot of O6-methylguanine-DNA-methyltransferase promoter methylation in oral squamous cell carcinoma
Click here to view |
 | Figure 10: Funnel plot of studies with O6-methylguanine-DNAmethyltransferase promoter methylation
Click here to view |
Correlation of studies with clinicopathological data
Yakushiji et al. reported that there was no statistical significance on comparing methylation of P16 with clinicopathological stages. [16]
Ogi et al. reported that methylation of P16 correlated with younger age (P = 0.043) and T-category (P = 0.038). [18]
Viswanathan et al. reported that abnormal methylation of P16 and MGMT was detected in tumors irrespective of stage and location in the oral cavity. [19]
Kulkarni and Saranath reported that there was no significant association between the clinicopathological profile of the patients, including the size of the tumor, presence of lymph node metastasis, differentiation of the tumors, tumor-node-metastasis staging of the cancer, and sex or age of the patients, and hypermethylation of P16, DAPK and MGMT. [20]
Ishida et al. reported that tumor size, degree of differentiation, clinical stage, and frequency of metastasis to nodes were significantly associated with hypermethylation of P16. He reported that there was no significant correlation between MGMT and clinicopathological factors. He also reported that an apparent correlation between overall gene hypermethylation status of P16 and MGMT, tobacco use, alcohol consumption, and concurrent exposure to both substances was observed. [21]
Kato et al. reported that there was no relationship between methylation status of P16 and MGMT with clinicopathological features. [23]
Sailasree et al. reported that promoter methylation of P16 was associated with tumor size, nodal involvement and increased disease recurrence. [24]
Supic et al. reported that there was no correlation of methylation status of P16, DAPK and MGMT genes with clinicopathological features but reported that hypermethylation of P16 gene promoter showed tendency of increase with age, with cutoff point selected according to the median value of 58. [25]
Kordi-Tamandani et al. reported that there was no correlation of methylation status of MGMT with clinical features (age and sex) and stages of cancer. He also reported that MGMT methylation may be considered as a potential molecular marker for the poor survival in advanced OSCC. [27]
Su et al. reported that the hypermethylation status of P16, DAPK and MGMT in tumors did not depend on clinicopathological features such as gender, lifestyle, tumor stage, recurrence, or histologic differentiation. Nevertheless, he reported that the mean age of patients with hypermethylated P16 was lesser than those without (P = 0.027). Multiple logistic regression predicted patients with hypermethylated P16 have higher risks of lymph node invasion (adjusted odds ratio [OR] = 6.21, P = 0.030) in young patients and distant metastasis (adjusted OR = 19.23, P = 0.007) in older patients. Moreover, P16 promoter hypermethylation was significantly associated with shortened disease-free survival (P = 0.034) in older patients. [28]
Kaur et al. reported that P16 promoter methylation was significantly associated with nodal involvement (P = 0.04, OR = 3.3, 95% CI = 1.1-10.2). [29]
Wong et al. reported that frequencies of P16, DAPK, and MGMT gene promoter hypermethylation did not differ based on the tumor site (P > 0.05). Promoter hypermethylation rates of the P16, DAPK, and MGMT genes were not correlated with tumor size, differentiation, betel nut chewing, tobacco smoking, or alcohol consumption (P > 0.05). Methylation rates of MGMT (50%) and DAPK (55.6%) in metastasized OSCC were higher than those of MGMT (23.9%) and DAPK (41.3%) in nonmetastasized OSCC. He also reported that hypermethylated P16 promoters were found in 63% of nonmetastasized tumors and in 77.8% of metastatic tumors (but was not statistically significant). [30]
| Discussion | | |
Oral squamous cell carcinoma is the sixth most common malignancy in the world. Due to its relative high mortality and low cure rate, OSCC represents a major health problem. Early detection of OSCC is important to reduce mortality rates and to help provide successful cancer treatment. Carcinogenesis is a multistep process. The genetic and epigenetic alterations are involved in the development and progression of OSCC.
Gene-specific promoter alterations are common epigenetic aberrations found in human tumors. Hypermethylation of CpG islands in promoter regions is one of the important mechanisms for inactivation of tumor-suppressor genes involving apoptosis, cell cycle control, DNA-repair, cell-cell adhesion and Wnt signaling. The prevalence of P16, DAPK and MGMT promoter hypermethylation in OSCC has been evaluated for several years while the results remain controversial.
The effects of methylation have been studied in various genes over recent years, extracting genetic material from cells in tumors and potentially malignant disorders, saliva, serum, or healthy tissue adjacent to the tumor. This is because methylation can be detected in tumors and potentially malignant disorders and even in clinically and histologically healthy tissue adjacent to the tumor, suggesting that methylation may occur early in oral carcinogenesis and might serve as an early marker of the disease. [39]
P16/INK4A is known as one the most important tumor-suppressor genes which plays an important role in regulating the cell cycle. Hypermethylation of the CDKN2A promoter region has been extensively evaluated in oral cancers with the frequency of hypermethylation being reported from 28% to 86%. [15],[20] Aberrant methylation of P16 gene has not been detected in noncancer controls. [19],[ 34]
Tran et al. reported that in betel chewing individuals with oral cancer, P16 methylation was detected in 63% of OSCCs and 67% of verrucous carcinomas. [22]
A correlation was also found between P16 methylation and higher-grade dysplasia. [35] In studies on precancerous lesions, it was reported that P16 methylation was not related to the malignant transformation of lichen planus but was significantly associated with the malignant transformation of leukoplakia, especially in relation to tobacco use. [6]
Death-associated protein kinase encodes a serine/threonine kinase that is required for apoptosis induced by IFN-g. Sanchez-Cespedes et al. reported that the promoter hypermethylation of DAPK has been associated with the formation of metastasis and advanced stages of cancer. [14]
Supic et al. reported that the detection of DAPK promoter hypermethylation at resection margins of oral tumors has been significantly associated with decreased overall survival, suggesting that it may have utility as a biomarker for guiding patient follow-up strategies.
O 6 -methylguanine-DNA-methyltransferase is a DNA-repair gene that protects from toxicity and mutations that occur by alkylating agents through the removal of O 6 -guanine-DNA adducts. MGMT hypermethylation has been reported for many cancer types.
Zuo et al. reported that MGMT promoter hypermethylation has also been associated with poorer outcomes for oral cancer, including a greater likelihood of nodal metastases, tumor recurrence, and decreased survival. [40]
Although many studies have reported the prevalence of P16, DAPK and MGMT gene hypermethylation in OSCC, the results remain inconclusive with the reasons of small sample size. Thus, a meta-analysis was performed by pooling data from published studies, which can increase the statistical power.
In the present study, a total of 16 articles were selected based on inclusion and exclusion criteria, from which the pooled prevalence of methylation in OSCC cases was calculated. Three separate meta-analysis was performed to assess the methylation status of P16, DAPK and MGMT genes in OSCC.
Our meta-analysis data of P16 methylation status showed that the overall estimated pooled prevalence of P16 methylation among 932 OSCC cases in 15 studies was 43% (CI = 40-46%). Heterogeneity of results among studies prevailed. From the present analysis, we found that Kulkarni and Saranath, Tran et al., Supic et al., Ohta et al. and Wong et al. studies showed a higher P16 methylation prevalence which range from 58% to 67% and Ogi et al., Viswanathan et al., Sailasree et al. and Su et al. studies showed a lower P16 methylation prevalence which range from 23% to 29%.
Our meta-analysis data of DAPK methylation status showed that the overall estimated pooled prevalence of DAPK methylation among 330 OSCC cases in five studies was 39.7% (CI = 15.0-64.3%). Heterogeneity of results among studies prevailed. From the present analysis, we found that Kulkarni and Saranath study showed a higher DAPK methylation prevalence which was 68.3% and Ogi et al. study showed a lower DAPK methylation prevalence which was 7% only.
Our meta-analysis data of MGMT methylation status showed that the overall estimated pooled prevalence of MGMT methylation among 509 OSCC cases in eight studies was 39.8% (CI = 25.2-54.3%). Heterogeneity of results among studies prevailed. From the present analysis, we found that Kulkarni and Saranath, Kato et al. and Kordi-Tamandani et al. studies showed a higher MGMT methylation prevalence which range from 52% to 74% and Ishida et al. and Su et al. studies showed a lower MGMT methylation prevalence which range from 12% to 21%.
The heterogeneity in methylation patterns in different studies may arise from difference in age, gender, ethnicity, and sample size, the location of the study group, smoking status, other adverse habits status, tumor stages, histopathology types and methods of methylation detection.
Despite significant epigenetic alterations found in OSCC, hypermethylation prevalences and correlations with the clinical outcomes of the disease in various studies are inconsistent. These differences probably reflect the heterogeneity of OSCC in their histology and clinical behavior, with different etiologies and associated risk factors, and known tissue and tumor-type specificity of methylation pattern. OSCCs originated from different locations of the oral region showed different methylation pattern.
The higher percentage of methylation in India may reflect the inherent differences in the prevalent molecular pathway in a majority of the chewing tobacco-associated cancers, as compared to oral cancers in USA, UK, Japan, and other developed countries, where the cancer is primarily associated with tobacco smoking and with/without alcohol consumption. [20]
To summarize, multiple studies show that a higher prevalence of methylation of P16, DAPK and MGMT occur in OSCC and the promoter hypermethylation of P16, DAPK and MGMT can be used for early detection of oral cancer and play a role in oral cancer progression.
Limitations of the review
We acknowledge the potential presence of publication bias within this review. The number of articles reviewed is minimal. This is due to the scarcity of studies available in promoter methylation pattern in OSCC. Our search also included publications in the English literature only. No unpublished data were included. The data used for pooled analysis were taken from published articles instead of original data. Further studies must be performed with similar outcome measures that could be compared in order to generate a more homogenous group of data. This could aid in giving better systematic reviews in the future in this field of study.
| Conclusion | | |
We can conclude from our systematic review that a higher prevalence of methylation of P16, DAPK and MGMT genes occur in OSCC cases. The promoter hypermethylation of P16, DAPK and MGMT genes play a role in oral cancer progression and can be used for early detection of oral cancer.
Heterogeneity in methylation patterns in different studies prevail which may arise from difference in age, gender, ethnicity, and sample size, the location of the study group, smoking status, other adverse habits status, tumor stages, histopathology types and methods of methylation detection.
Further studies must be performed with large sample sizes and with similar outcome measures that could be compared in order to generate a more homogenous group of data. This could aid in giving better systematic reviews in the future in this field of study.
| References | | |
| 1. | Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W, et al. Stromal features are predictive of disease mortality in oral cancer patients. J Pathol 2011;223:470-81.  |
| 2. | Mydlarz WK, Hennessey PT, Califano JA. Advances and perspectives in the molecular diagnosis of head and neck cancer. Expert Opin Med Diagn 2010;4:53-65. |
| 3. | Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96. |
| 4. | Hashibe M, Brennan P, Chuang SC, Boccia S, Castellsague X, Chen C, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev 2009;18:541-50. |
| 5. | Dayyani F, Etzel CJ, Liu M, Ho CH, Lippman SM, Tsao AS. Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head Neck Oncol 2010;2:15. |
| 6. | Lingen MW, Pinto A, Mendes RA, Franchini R, Czerninski R, Tilakaratne WM, et al. Genetics/epigenetics of oral premalignancy: Current status and future research. Oral Dis 2011;17 Suppl 1:7-22. |
| 7. | Saintigny P, Zhang L, Fan YH, El-Naggar AK, Papadimitrakopoulou VA, Feng L, et al. Gene expression profiling predicts the development of oral cancer. Cancer Prev Res (Phila) 2011;4:218-29. |
| 8. | Kyrgidis A, Tzellos TG, Triaridis S. Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications. J Carcinog 2010;9:3. [ PUBMED]  |
| 9. | Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 2002;99:3740-5. |
| 10. | Shaw R. The epigenetics of oral cancer. Int J Oral Maxillofac Surg 2006;35:101-8. |
| 11. | Huang SH, Lee HS, Mar K, Ji DD, Huang MS, Hsia KT. Loss expression of O6-methylguanine DNA methyltransferase by promoter hypermethylation and its relationship to betel quid chewing in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:883-9. |
| 12. | Sharma S, Salehi F, Scheithauer BW, Rotondo F, Syro LV, Kovacs K. Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer Res 2009;29:3759-68. |
| 13. | Michie AM, McCaig AM, Nakagawa R, Vukovic M. Death-associated protein kinase (DAPK) and signal transduction: Regulation in cancer. FEBS J 2010;277:74-80. |
| 14. | Sanchez-Cespedes M, Esteller M, Wu L, Nawroz-Danish H, Yoo GH, Koch WM, et al. Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res 2000;60:892-5. |
| 15. | Nakahara Y, Shintani S, Mihara M, Ueyama Y, Matsumura T. High frequency of homozygous deletion and methylation of P16(INK4A) gene in oral squamous cell carcinomas. Cancer Lett 2001;163:221-8. |
| 16. | Yakushiji T, Noma H, Shibahara T, Arai K, Yamamoto N, Tanaka C, et al. Analysis of a role for P16/CDKN2 expression and methylation patterns in human oral squamous cell carcinoma. Bull Tokyo Dent Coll 2001;42:159-68. |
| 17. | Huang MJ, Yeh KT, Shih HC, Wang YF, Lin TH, Chang JY, et al. The correlation between CpG methylation and protein expression of P16 in oral squamous cell carcinomas. Int J Mol Med 2002;10:551-4. |
| 18. | Ogi K, Toyota M, Ohe-Toyota M, Tanaka N, Noguchi M, Sonoda T, et al. Aberrant methylation of multiple genes and clinicopathological features in oral squamous cell carcinoma. Clin Cancer Res 2002;8:3164-71. |
| 19. | Viswanathan M, Tsuchida N, Shanmugam G. Promoter hypermethylation profile of tumor-associated genes P16, p15, hMLH1, MGMT and E-cadherin in oral squamous cell carcinoma. Int J Cancer 2003;105:41-6. |
| 20. | Kulkarni V, Saranath D. Concurrent hypermethylation of multiple regulatory genes in chewing tobacco associated oral squamous cell carcinomas and adjacent normal tissues. Oral Oncol 2004;40:145-53. |
| 21. | Ishida E, Nakamura M, Ikuta M, Shimada K, Matsuyoshi S, Kirita T, et al. Promotor hypermethylation of p14ARF is a key alteration for progression of oral squamous cell carcinoma. Oral Oncol 2005;41:614-22. |
| 22. | Tran TN, Liu Y, Takagi M, Yamaguchi A, Fujii H. Frequent promoter hypermethylation of RASSF1A and P16INK4a and infrequent allelic loss other than 9p21 in betel-associated oral carcinoma in a Vietnamese non-smoking/non-drinking female population. J Oral Pathol Med 2005;34:150-6. |
| 23. | Kato K, Hara A, Kuno T, Mori H, Yamashita T, Toida M, et al. Aberrant promoter hypermethylation of P16 and MGMT genes in oral squamous cell carcinomas and the surrounding normal mucosa. J Cancer Res Clin Oncol 2006;132:735-43. |
| 24. | Sailasree R, Abhilash A, Sathyan KM, Nalinakumari KR, Thomas S, Kannan S. Differential roles of P16INK4A and p14ARF genes in prognosis of oral carcinoma. Cancer Epidemiol Biomarkers Prev 2008;17:414-20. |
| 25. | Supic G, Kozomara R, Brankovic-Magic M, Jovic N, Magic Z. Gene hypermethylation in tumor tissue of advanced oral squamous cell carcinoma patients. Oral Oncol 2009;45:1051-7. |
| 26. | Ohta S, Uemura H, Matsui Y, Ishiguro H, Fujinami K, Kondo K, et al. Alterations of P16 and p14ARF genes and their 9p21 locus in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:81-91. |
| 27. | Kordi-Tamandani DM, Moazeni-Roodi AK, Rigi-Ladiz MA, Hashemi M, Birjandian E, Torkamanzehi A. Promoter hypermethylation and expression profile of MGMT and CDH1 genes in oral cavity cancer. Arch Oral Biol 2010;55:809-14. |
| 28. | Su PF, Huang WL, Wu HT, Wu CH, Liu TY, Kao SY. P16(INK4A) promoter hypermethylation is associated with invasiveness and prognosis of oral squamous cell carcinoma in an age-dependent manner. Oral Oncol 2010;46:734-9. |
| 29. | Kaur J, Demokan S, Tripathi SC, Macha MA, Begum S, Califano JA, et al. Promoter hypermethylation in Indian primary oral squamous cell carcinoma. Int J Cancer 2010;127:2367-73. |
| 30. | Wong YK, Lee LT, Liu CJ. Hypermethylation of MGMT and DAPK gene promoters is associated with tumorigenesis and metastasis in oral squamous cell carcinoma. J Dent Sci 2011;6:158-64. |
| 31. | Watts GS, Pieper RO, Costello JF, Peng YM, Dalton WS, Futscher BW. Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol Cell Biol 1997;17:5612-9. |
| 32. | Lo YM, Wong IH, Zhang J, Tein MS, Ng MH, Hjelm NM. Quantitative analysis of aberrant P16 methylation using real-time quantitative methylation-specific polymerase chain reaction. Cancer Res 1999;59:3899-903. |
| 33. | Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 2000;60:2368-71. |
| 34. | Shaw RJ, Liloglou T, Rogers SN, Brown JS, Vaughan ED, Lowe D, et al. Promoter methylation of P16, RARbeta, E-cadherin, cyclin A1 and cytoglobin in oral cancer: Quantitative evaluation using pyrosequencing. Br J Cancer 2006;94:561-8. |
| 35. | Ruesga MT, Acha-Sagredo A, Rodríguez MJ, Aguirregaviria JI, Videgain J, Rodríguez C, et al. P16(INK4a) promoter hypermethylation in oral scrapings of oral squamous cell carcinoma risk patients. Cancer Lett 2007;250:140-5. |
| 36. | Sawhney M, Rohatgi N, Kaur J, Gupta SD, Deo SV, Shukla NK, et al. MGMT expression in oral precancerous and cancerous lesions: Correlation with progression, nodal metastasis and poor prognosis. Oral Oncol 2007;43:515-22. |
| 37. | Supic G, Kozomara R, Jovic N, Zeljic K, Magic Z. Prognostic significance of tumor-related genes hypermethylation detected in cancer-free surgical margins of oral squamous cell carcinomas. Oral Oncol 2011;47:702-8. |
| 38. | Deep JS, Sidhu S, Chandel A, Thapliyal S, Garg C, "Aberrant Methylation in Promoters of GSTP1, p16, p14, and RASSF1A Genes in Smokers of North India," ISRN Pulmonology, vol. 2012, Article ID 247631, 6 pages, 2012. doi:10.5402/2012/247631. |
| 39. | Ha PK, Califano JA. Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol 2006;7:77-82. |
| 40. | Zuo C, Ai L, Ratliff P, Suen JY, Hanna E, Brent TP, et al. O6-methylguanine-DNA methyltransferase gene: Epigenetic silencing and prognostic value in head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 2004;13:967-75. |
Correspondence Address:
K R Don
Department of Oral and Maxillofacial Pathology, Saveetha Dental College, Chennai, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0970-9290.152208
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5] |
|
| This article has been cited by | | 1 |
hnRNP K induces HPV16 oncogene expression and promotes cervical cancerization |
|
| Yuanjing Lyu, Li Song, Rui Mao, Chunliang Liu, Meijuan Feng, Caihong Wu, Ruixin Pei, Ling Ding, Jintao Wang | | Journal of Cancer Research and Clinical Oncology. 2023; | | [Pubmed] | [DOI] | | | 2 |
DNA methylation in the genesis, progress and prognosis of head and neck cancer |
|
| Zijian Guo, Wenwen Liu, Yuhan Yang, Shunhao Zhang, Chunjie Li, Wenbin Yang | | Holistic Integrative Oncology. 2023; 2(1) | | [Pubmed] | [DOI] | | | 3 |
Methylation of tumour suppressor genes in benign and malignant salivary gland tumours: a systematic review and meta-analysis |
|
| Nadja Nikolic, Jelena Carkic, Jelena Jacimovic, Aleksandar Jakovljevic, Boban Anicic, Zoran Jezdic, Jelena Milasin | | Epigenetics. 2022; : 1 | | [Pubmed] | [DOI] | | | 4 |
Hallmarks of Cancer Applied to Oral and Oropharyngeal Carcinogenesis: A Scoping Review of the Evidence Gaps Found in Published Systematic Reviews |
|
| Miguel Ángel González-Moles, Saman Warnakulasuriya, María López-Ansio, Pablo Ramos-García | | Cancers. 2022; 14(15): 3834 | | [Pubmed] | [DOI] | | | 5 |
Head and Neck Cancers Are Not Alike When Tarred with the Same Brush: An Epigenetic Perspective from the Cancerization Field to Prognosis |
|
| Diego Camuzi, Tatiana de Almeida Simão, Fernando Dias, Luis Felipe Ribeiro Pinto, Sheila Coelho Soares-Lima | | Cancers. 2021; 13(22): 5630 | | [Pubmed] | [DOI] | | | 6 |
Immunohistochemical expression of P16 and ß-catenin in oral submucous fibrosis and oral squamous cell carcinoma with or without coexistence of oral submucous fibrosis |
|
| Archana Sudhakaran, Kaveri Hallikeri, Roshni Monteiro | | Clinical Cancer Investigation Journal. 2021; 10(4): 189 | | [Pubmed] | [DOI] | | | 7 |
Improved local control in p16 negative oropharyngeal cancers with hypermethylated MGMT |
|
| Garrett L. Jensen, Gabriel Axelrud, David Fink, Kendall Hammonds, Kimberly Walker, Marcus Volz, Alan Gowan, Arundhati Rao, Niloyjyoti Deb, Sameer G. Jhavar | | Radiotherapy and Oncology. 2021; 157: 234 | | [Pubmed] | [DOI] | | | 8 |
Assessing Frozen Section Surgical Margin Status in Oral Squamous Cell Carcinoma |
|
| Deep R. Viswasini, Kanchi Ravi Don, Herald J. Sherlin, Gifrina Jayaraj, Archana Santhanam | | Journal of Evolution of Medical and Dental Sciences. 2021; 10(42): 3623 | | [Pubmed] | [DOI] | | | 9 |
Methylation status of p16INK4a and p14ARF gene in saliva of smokeless tobacco users: A pilot descriptive study |
|
| Priyadharshini Ramakrishnan, Sujatha S, Paramita Kundu | | Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 2021; 33(2): 221 | | [Pubmed] | [DOI] | | | 10 |
Knowledge and Attitude of Family Members of Patients of Oral Squamous Cell Carcinoma - A Survey |
|
| Suvarna Kizhakkoottu, Don K. R. , Herald J. Sherlin, Gifrina Jayaraj, Archana Santhanam | | Journal of Evolution of Medical and Dental Sciences. 2020; 9(52): 3982 | | [Pubmed] | [DOI] | | | 11 |
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 |
|
| Xiang-Yu Liyanage,Xiang-Yu Wathupola,Xiang-Yu Muraleetharan,Xiang-Yu Perera,Xiang-Yu Punyadeera,Xiang-Yu Udagama | | Biomolecules. 2019; 9(4): 148 | | [Pubmed] | [DOI] | | | 12 |
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 |
|
| Xiang-Yu Liyanage,Xiang-Yu Wathupola,Xiang-Yu Muraleetharan,Xiang-Yu Perera,Xiang-Yu Punyadeera,Xiang-Yu Udagama | | Biomolecules. 2019; 9(4): 148 | | [Pubmed] | [DOI] | | | 13 |
Epigenetic Modifications in Head and Neck Cancer |
|
| Jadwiga Gazdzicka,Karolina Golabek,Joanna Katarzyna Strzelczyk,Zofia Ostrowska | | Biochemical Genetics. 2019; | | [Pubmed] | [DOI] | | | 14 |
Epigenetic Modifications in Head and Neck Cancer |
|
| Jadwiga Gazdzicka,Karolina Golabek,Joanna Katarzyna Strzelczyk,Zofia Ostrowska | | Biochemical Genetics. 2019; | | [Pubmed] | [DOI] | | | 15 |
Clinical and Molecular Characterization of Surgically Treated Oropharynx Squamous Cell Carcinoma Samples |
|
| Ana Carolina de Carvalho,Matias Eliseo Melendez,Cristina da Silva Sabato,Edenir Inez Palmero,Lidia Maria Rebolho Batista Arantes,Cristovam Scapulatempo Neto,André Lopes Carvalho | | Pathology & Oncology Research. 2019; 25(3): 1047 | | [Pubmed] | [DOI] | | | 16 |
Clinical and Molecular Characterization of Surgically Treated Oropharynx Squamous Cell Carcinoma Samples |
|
| Ana Carolina de Carvalho,Matias Eliseo Melendez,Cristina da Silva Sabato,Edenir Inez Palmero,Lidia Maria Rebolho Batista Arantes,Cristovam Scapulatempo Neto,André Lopes Carvalho | | Pathology & Oncology Research. 2019; 25(3): 1047 | | [Pubmed] | [DOI] | | | 17 |
Promotor hypermethylated genes: Prospective diagnostic biomarkers in oral cancerogenesis |
|
| Suzana Dvojakovska,Danica Popovic-Monevska,Aleksandar Grcev,Goran Pancevski,Alberto Benedetti,Vladimir Popovski,Aleksandar Dimovski,Aleksandar Stamatoski | | Journal of Cranio-Maxillofacial Surgery. 2018; 46(10): 1737 | | [Pubmed] | [DOI] | | | 18 |
Promotor hypermethylated genes: Prospective diagnostic biomarkers in oral cancerogenesis |
|
| Suzana Dvojakovska,Danica Popovic-Monevska,Aleksandar Grcev,Goran Pancevski,Alberto Benedetti,Vladimir Popovski,Aleksandar Dimovski,Aleksandar Stamatoski | | Journal of Cranio-Maxillofacial Surgery. 2018; 46(10): 1737 | | [Pubmed] | [DOI] | | | 19 |
Effect of TET1 regulating MGMT on chemotherapy resistance of oral squamous cell carcinoma stem cells |
|
| Wei Wang,Xin Li,Fan Wang,Xiang-Yu Sun | | Journal of Cellular Biochemistry. 2018; 119(1): 723 | | [Pubmed] | [DOI] | | | 20 |
PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential |
|
| Bharath K. Velmurugan,Chien-Hung Lee,Shang-Lun Chiang,Chun-Hung Hua,Mei-Chung Chen,Shu-Hui Lin,Kun-Tu Yeh,Ying-Chin Ko | | Journal of Cellular Physiology. 2018; 233(2): 1300 | | [Pubmed] | [DOI] | | | 21 |
PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential |
|
| Bharath K. Velmurugan,Chien-Hung Lee,Shang-Lun Chiang,Chun-Hung Hua,Mei-Chung Chen,Shu-Hui Lin,Kun-Tu Yeh,Ying-Chin Ko | | Journal of Cellular Physiology. 2018; 233(2): 1300 | | [Pubmed] | [DOI] | | | 22 |
Study on expression of p16 and human papillomavirus 16 and 18 (E6) in OLP and its malignant transformation |
|
| Ting Liu,Hong Zhang,Xuesong Yang,Xiaojie Li,Yi Shi,Weidong Niu,Tingjiao Liu | | Pathology - Research and Practice. 2018; 214(2): 296 | | [Pubmed] | [DOI] | | | 23 |
Study on expression of p16 and human papillomavirus 16 and 18 (E6) in OLP and its malignant transformation |
|
| Ting Liu,Hong Zhang,Xuesong Yang,Xiaojie Li,Yi Shi,Weidong Niu,Tingjiao Liu | | Pathology - Research and Practice. 2018; 214(2): 296 | | [Pubmed] | [DOI] | | | 24 |
Associations of RASSF1A, RARß, and CDH1 promoter hypermethylation with oral cancer risk |
|
| Guohong Wen,Huadong Wang,Zhaohui Zhong | | Medicine. 2018; 97(11): e9971 | | [Pubmed] | [DOI] | | | 25 |
Associations of RASSF1A, RARß, and CDH1 promoter hypermethylation with oral cancer risk |
|
| Guohong Wen,Huadong Wang,Zhaohui Zhong | | Medicine. 2018; 97(11): e9971 | | [Pubmed] | [DOI] | | | 26 |
Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification |
|
| Marc L Ooft,Jolique van Ipenburg,Rob van Loo,Rick de Jong,Cathy Moelans,Weibel Braunius,Remco de Bree,Paul van Diest,Senada Koljenovic,Rob Baatenburg de Jong,Jose Hardillo,Stefan M Willems | | Journal of Clinical Pathology. 2018; 71(4): 351 | | [Pubmed] | [DOI] | | | 27 |
Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification |
|
| Marc L Ooft,Jolique van Ipenburg,Rob van Loo,Rick de Jong,Cathy Moelans,Weibel Braunius,Remco de Bree,Paul van Diest,Senada Koljenovic,Rob Baatenburg de Jong,Jose Hardillo,Stefan M Willems | | Journal of Clinical Pathology. 2018; 71(4): 351 | | [Pubmed] | [DOI] | | | 28 |
Prognostic role of tumor infiltrating lymphocytes in EBV positive and EBV negative nasopharyngeal carcinoma |
|
| Marc L. Ooft,Jolique A. van Ipenburg,Weibel W. Braunius,Charlotte I. Zuur,Senada Koljenovic,Stefan M. Willems | | Oral Oncology. 2017; 71: 16 | | [Pubmed] | [DOI] | | | 29 |
Prognostic role of tumor infiltrating lymphocytes in EBV positive and EBV negative nasopharyngeal carcinoma |
|
| Marc L. Ooft,Jolique A. van Ipenburg,Weibel W. Braunius,Charlotte I. Zuur,Senada Koljenovic,Stefan M. Willems | | Oral Oncology. 2017; 71: 16 | | [Pubmed] | [DOI] | | | 30 |
MicroRNA-542-3p inhibits oral squamous cell carcinoma progression by inhibiting ILK/TGF-ß1/Smad2/3 signaling |
|
| Bin Qiao, Jing-Hua Cai, Alfred King-Yin Lam, Bao-Xia He | | Oncotarget. 2017; 8(41): 70761 | | [Pubmed] | [DOI] | | | 31 |
Interaction Between Rare Variants in NOTCH1 and Betel Quid Chewing in Oral Squamous Cell Carcinoma |
|
| Chia-Min Chung,Chien-Hung Lee,Mu-Kuan Chen,Ming-Hsui Tsai,Ying-Chin Ko | | Genetic Testing and Molecular Biomarkers. 2017; 21(10): 608 | | [Pubmed] | [DOI] | | | 32 |
Interaction Between Rare Variants in NOTCH1 and Betel Quid Chewing in Oral Squamous Cell Carcinoma |
|
| Chia-Min Chung,Chien-Hung Lee,Mu-Kuan Chen,Ming-Hsui Tsai,Ying-Chin Ko | | Genetic Testing and Molecular Biomarkers. 2017; 21(10): 608 | | [Pubmed] | [DOI] | | | 33 |
Promoter hypermethylation of PTPL1, PTPN6, DAPK, p16 and 5-azacitidine inhibits growth in DLBCL |
|
| WENMING WANG,JING WANG,ZHENGQIAN LI,MINGXIA ZHU,ZHE ZHANG,YANFANG WANG,HONGMEI JING | | Oncology Reports. 2016; 35(1): 139 | | [Pubmed] | [DOI] | | | 34 |
Promoter hypermethylation of PTPL1, PTPN6, DAPK, p16 and 5-azacitidine inhibits growth in DLBCL |
|
| WENMING WANG,JING WANG,ZHENGQIAN LI,MINGXIA ZHU,ZHE ZHANG,YANFANG WANG,HONGMEI JING | | Oncology Reports. 2016; 35(1): 139 | | [Pubmed] | [DOI] | | | 35 |
Heterogeneous nuclear ribonucleoprotein K is overexpressed and associated with poor prognosis in gastric cancer |
|
| Ruirui Yang,Ying Zeng,Haifan Xu,Zhuo Chen,Mengqin Xiang,Yun Fu,Yufang Yin,Jing Zhong,Min Zeng,Peihua Wang,Qin You,Xi Zeng | | Oncology Reports. 2016; 36(2): 929 | | [Pubmed] | [DOI] | | | 36 |
Heterogeneous nuclear ribonucleoprotein K is overexpressed and associated with poor prognosis in gastric cancer |
|
| Ruirui Yang,Ying Zeng,Haifan Xu,Zhuo Chen,Mengqin Xiang,Yun Fu,Yufang Yin,Jing Zhong,Min Zeng,Peihua Wang,Qin You,Xi Zeng | | Oncology Reports. 2016; 36(2): 929 | | [Pubmed] | [DOI] | |
|
|
|
|
|
|
|
|
|
|
Users online:
