|Year : 2017 | Volume
| Issue : 6 | Page : 214-218
Biomarkers in molecular epidemiology study of oral squamous cell carcinoma in the era of precision medicine
Qing-Hao Zhu1, Qing-Chao Shang1, Zhi-Hao Hu1, Yuan Liu2, Bo Li1, Bo Wang1, An-Hui Wang1
1 Department of Epidemiology, School of Public Health, Fourth Military Medical University, Xi'an, China
2 Department of Outpatient, Xi'an Communication College, Xi'an, Shaanxi, China
|Date of Web Publication||29-Dec-2017|
Dr. An-Hui Wang
Department of Epidemiology, School of Public Health, Fourth Military Medical University, Xi'an 710032, Shaanxi
Source of Support: None, Conflict of Interest: None
Oral cancer, which occurs in the mouth, lips, and tongue, is a multifactorial disease whose etiology involves environment, genetic, and epigenetic factors. Tobacco use and alcohol consumption are regarded as the primary risk factors for oral squamous cell carcinoma (OSCC), and betel use, other chemicals, radiation, environmental, and genetics are reported as relevant risk factors for oral carcinogenesis. The human papillomavirus infection is an independent risk factor. Traditional epidemiology studies have revealed that environmental carcinogens are risk factors for OSCC. Molecular epidemiology studies have revealed that the susceptibility to OSCC is influenced by both environmental and genetic risk factors. However, the details and mechanisms of risk factors involved in OSCC are unclear. Advanced methods and techniques used in human genome studies provide great opportunities for researchers to explore and identify (a) the details of such risk factors and (b) genetic susceptibility involved in OSCC. Human genome epidemiology is a new branch of epidemiology, which leads the epidemiology study from the molecular epidemiology era into the era of genome-wide association study. In the era of precision medicine, molecular epidemiology studies should focus on biomarkers for cancer genomics and their potential utility in clinical practice. Here, we briefly reviewed several molecular epidemiology studies of OSCC, focusing on biomarkers as valuable utility in risk assessment, clinical screening, diagnosis, and prognosis prediction of OSCC in the era of precision medicine.
Keywords: Biomarker, epidemiology, molecular, oral cancer
|How to cite this article:|
Zhu QH, Shang QC, Hu ZH, Liu Y, Li B, Wang B, Wang AH. Biomarkers in molecular epidemiology study of oral squamous cell carcinoma in the era of precision medicine. Cancer Transl Med 2017;3:214-8
|How to cite this URL:|
Zhu QH, Shang QC, Hu ZH, Liu Y, Li B, Wang B, Wang AH. Biomarkers in molecular epidemiology study of oral squamous cell carcinoma in the era of precision medicine. Cancer Transl Med [serial online] 2017 [cited 2018 Oct 17];3:214-8. Available from: http://www.cancertm.com/text.asp?2017/3/6/214/221914
| Introduction|| |
Oral cancer, which occurs in the mouth, lips, and tongue, causes significant morbidity and mortality, particularly in populations of low socioeconomic status., Data from the World Health Organization demonstrated that there are an estimated 529,000 new cases of oral cavity and pharynx cancers, and more than 300,000 deaths are caused by oral cancer each year. There were an estimated 300,383 global cases of lip and oral cavity cancer in 2012, with more than half of the cases located in Asia area. Two-thirds of the global cases of oral cancers are reported in low- and middle-income countries, where half of those cases occur in South Asia. One-fifth of all oral cancer cases and one-fourth of all oral cancer deaths occur in India.
Oral cancer is a multifactorial disease, and risk factors include environmental risk factors, genetic susceptibility, and epigenetic risk factors., The human papillomavirus (HPV) infection is considered an independent risk factor involved in oral cancer. Incidence rates of oral cancer vary widely throughout the world due to oral cancer-associated behaviors including alcohol consumption, tobacco smoking, betel quid chewing, and smokeless tobacco using.,,,
The main histologic type of oral cancer is squamous cell carcinoma (SCC) which accounts for nearly 90% of all oral cancer cases. The risk factors for oral SCC (OSCC) include exposure to tobacco smoking and alcohol drinking. HPV infection also increased the risk for OSCC. HPV16 accounts for 90%–95% of HPV-positive OPSCC cases.,,
Traditional epidemiology studies have identified that environmental carcinogens play a critical role in the process of OSCC.,,,,, Molecular epidemiology studies have revealed that the susceptibility of OSCC is associated with both genomic and nongenomic factors and involves an interaction between genomic and nongenomic factors. Human genome epidemiology (HuGE) is denoted as “an emerging field of inquiry that uses systematic applications of epidemiologic methods and approaches in population-based studies of the impact of human genetic variation on health and disease.” A key characteristic of HuGE is the molecular biological techniques applied in studies, especially those using DNA microarray chips in genome-wide association studies (GWASs). These techniques can compare millions of single nucleotide polymorphisms (SNPs) between genome DNA from cases and controls. In this review, we focus on the molecular epidemiology studies of OSCC.
| Precision Medicine and Molecular Epidemiology|| |
Precision medicine is a medical model which focuses on two parts: cancer genomic utility and generating big data of health and disease based on national cohort studies. In this model, individuals' cancer genomic utility includes risk assessment, clinical screening, diagnosis, treatment, and prognosis prediction.
The integration of biomarkers of exposure, susceptibility, and outcomes into epidemiologic research has been referred to as “molecular epidemiology.” Molecular epidemiology is the study of gene-disease associations as well as gene-gene and gene-environment interactions using conventional epidemiologic study designs (case serial studies, cross-sectional studies, case–control studies, cohort studies, prognosis studies, etc.) combined with biomarkers. Molecular epidemiological studies in oral cancer attempt to elucidate biomarkers of exposure and susceptibility, which are involved in the process of oral cancer. Polymorphisms of genes that involved in the process of carcinogenesis as genetic susceptibility biomarkers have the potential to increased cancer risks among certain individuals. Rapid advances in human genomics are making it possible to develop detailed profiles of genetic susceptibility based on genetic variants in multiple pathways. Molecular biomarkers including gene metabolism, DNA repair, cell cycle, and immune status have the potential to increase our understanding of cancer etiology and develop possible prevention strategies.
| Current Status of Molecular Epidemiology Study in Oral Squamous Cell Carcinoma|| |
Biomarkers can be used for individualized assessment in multiple clinical settings, including disease risk management and distinguishing benign from malignant tissues. Biomarkers can be classified based on the disease state, including predictive, diagnostic, and prognostic biomarkers. A prognostic biomarker informs about a likely cancer outcome. Oral cancer biomarkers may be molecular such as genetic mutations, polymorphisms of genes, DNA copy number variance, telomere instabilities, and cell-cycle signaling pathways that are involved in oral cancer. Potential biomarkers include the growth signaling oncogenes, epidermal growth factor receptor (EGFR) and cyclin D1, the antigrowth signaling components p53 and p21, apoptotic effectors such as Bcl-2 and also components involved in angiogenesis, invasion, and metastasis processes were discussed.,,,
OSCC is the dominant type of oral cancer. It is a highly complex, multifocal process involving many factors, including tobacco smoking, alcohol drinking, and genetic susceptibility, which are all involved in disease progression.,, GWASs have been conducted as a powerful method to screening novel genetic markers related to increased susceptibility for diseases. rs3828805 (HLA-DQB1), rs201982221 (LHPP), and rs1453414 (OR52N2/TRIM5) have been shown to be associated with oral and pharyngeal cancers. rs6547741 (GPN1), rs928674 (LAMC3), rs8181047 (CDKN2B-AS1), and rs10462706 (CLPTM1L) have been shown to be associated with oral cancer. GWASs were carried out to study the genetic susceptibility of salivary gland carcinomas (SGC), OSCC,,, tongue SCC cells,, and laryngeal SCC. Further, genome-wide disease association studies in chewing tobacco-associated oral cancers have explored gene-environment interactions.
Overexpression of maltase-glucoamylase alpha-glucosidase (MGAM) and ADAM metallopeptidase domain 9 (ADAM9) genes are biological markers for OSCC. CYP1A1, CYP2E1, GSTM3, and NAT2 polymorphisms and their association with oral cancer risk were discussed, and NAT2 polymorphism and GSTM3 have been shown to be associated with the susceptibility to oral cancer. SNPs are one of the most used biomarkers indicating genetic variation, associated with susceptibility and prognoses of oral cancer. Polymorphisms in GSTT1, GSTM1, CYP2E1, CYP1A2, ADH1C, and MTHFR have been studied.,, Polymorphisms of DNA repair genes have been shown to be related with cancer susceptibility. The association between polymorphisms in DNA repair genes (XRCC1; XRCC3; XPC; XPD; and MGMT and OSCC) in a Thai population was discussed, and the variant genotypes with XRCC3 241Met and possibly XRCC1 194Trp and XPD exon 6 were associated with OSCC. In general, these SNPs influence the repair of DNA damage that is caused by environmental risk factors for oral cancer.
Individuals with increased risk for oral cancer have been shown to have rs9849237 CC and rs243865 CT genotypes, whereas rs9849237 CT, rs243865 CC, and rs10090787 CC genotypes indicated decreased risk of oral cancer. Individuals carrying rs9849237 CC or rs243865 CT had increased risk of oral cancer while individuals carrying rs10090787 CC had decreased risk of oral cancer. rs174549 in the fatty acid desaturase 1 (FADS1) gene has been shown to be strongly associated with laryngeal SCC risk. The FADS1 gene is located on chromosome 11q12-q13.1, which plays an important role in polyunsaturated fatty acid metabolism.
Aberrant DNA methylation is often observed in TSCC tissue and plays an important role in the development of TSCC. Significant genome-wide associations with SGC in non-Hispanic whites has been shown to detect SNPs in CHRNA2, OR4F15, ZNF343, and PARP4. With a view to identify genomic risk variants in chewing tobacco-associated oral cancer patients, a GWAS was conducted in patients of Indian ethnicity with long-term tobacco chewing habit. Methylation changes in promoters of immune-related genes may serve as potential molecular marker to define risk and to monitor the prognosis of OSCC patients in India, where genetic polymorphisms of TLR1, TLR2, TLR4, TLR6, TLR9, and TLR10 were genotyped and analyzed. Individuals with the variant A of the SNP TLR2-rs4696480 polymorphism demonstrated an increased risk of OSCC and OLL. This may also prove the feasibility of TLR polymorphisms as risk biomarkers for oral and laryngeal cancer. CD166 has been considered a relatively specific marker of stem cells and cancer stem cells, and the altered expression of CD166 has also been reported as a prognostic marker of several other types of cancer. CD166 has been shown to significantly enhance EGFR phosphorylation and prolonged EGF/EGFR signaling activation. CD166 is a potential therapeutic target for patients suffering from OSCC.
Polymorphisms of DNA repair genes and genetic susceptibility of OSCC are associated. SNPs in genes that encode proteins involved in inflammation and immunomodulation (IL1a, IL1b, IL8, and TNFα) have been shown to influence susceptibility of OSCC in Thailand. Evidence has indicated that the rs1412115 (AA and AG vs. GG) increases the risk of OSCC in Chinese Han populations. Data on VEGF polymorphisms as effect modifiers for OSCC have been pooled analyzed. SERPINB9 ranked first in the candidate gene list and contained a significant haplotype TAGGA. The second risk gene was SERPINE2 with the haplotype GGGCCCTTT, which was similar to the SERPINB9. Copy number alterations (CNAs) as candidate molecular biomarkers for OSCC were explored using high-resolution array comparative genomic hybridization (aCGH) technique. The MGAM and ADAM9 genes may be used as biological markers for OSCC. CDKN2A/p16 has been found to be inactivated in a broad spectrum of solid tumors and in more than 80% of OSCC. Molecular alteration of CDKN2A/p16 in progression of OSCC can pose an important tool for the prognosis of SCC.
| Biomarkers With Potential Clinical Utility in Oral Squamous Cell Carcinoma|| |
MicroRNAs (miRNAs) have gained attention as potential valuable biomarkers for carcinogenesis. Several altered miRNAs seem to play critical roles in the initiation and progression of OSCC by functioning either as oncogenes or as tumor suppressors. HPV infection leads to expression of cellular oncogenic and tumor suppressive miRNAs. miRNAs in human saliva as biomarkers for OSCC diagnosis purposes have been discussed., Circulating miRNAs from blood, serum, and plasma had been investigated in patients with OSCC. Specific miRNAs identified from samples (tissues, serum, plasma, or saliva) might have a potential clinical utility in the diagnosis, prognosis, and therapeutic targets of OSCC. The identified miRNAs may pave the way for future clinical use in the diagnosis, prognosis, and treatment of OSCC.
A regulatory network of lncRNAs-miRNAs-mRNAs in OSCC was discussed and shown to uncover the pathogenesis of OSCC, possibly providing potential therapeutic targets. Epigenetic changes are potentially reversible. Changes of small noncoding RNAs, histone modification, and DNA methylation are examples of epigenetic changes. New insights of the epigenetic processes that relate to OSCC are histone variants and long noncoding RNAs. In oral cancer, epigenetic alterations have been reported, in particular DNA methylation.,, Epigenetic biomarkers have been shown to be potential candidates for diagnosis, prognosis, and therapeutic targets in oral cancer. Saliva can be considered as a mirror of body health; the importance of salivary transcriptomes in oral cancer detection have been reviewed in detail.
Biomarkers of OSCC can provide key information for precision medicine as screening agents, diagnostic tools, personalized treatment avenues, and prognostic predictors. Biological markers in salivary of head and neck carcinoma have been reviewed. A prognostic DNA methylation profile of oral tongue SCC (OTSCC) was examined with the Illumina Human Methylation 450K (HM450K) array. These results suggest that DNA methylation in isolation is not likely to be of prognostic value and larger cohorts are required to identify such a biomarker for OTSCC. Hypermethylated ZNF582 and PAX1 have been shown to be effective biomarkers for the detection of oral dysplasia and oral cancer as well as for the prediction of oral cancer recurrence. CNAs in 75 OSCC cases were detected using an aCGH method, demonstrating the relationship between CNAs and clinical characteristics of OSCC. With genome-scale assessment of DNA methylation using HM450K in one of the largest OTSCC cohorts to date, no evidence was found to identify a hypermethylated group of tumors or a prognostic methylation signature.
RNA-based diagnosis and prognosis of oral cancer using noninvasive methods  and prognostic biomarkers in OSCC were reviewed. Macrophage polarization was discussed as a prognostic biomarker of patients in early stage of OSCC. M2 polarization of macrophages of OSCC patients has been shown to be correlated with increased dedifferentiation. Individuals with p16 expressing oropharyngeal squamous cell cancers have favorable clinical outcomes and prognosis.
The practice of precision medicine for oral cancers should focus not only on the biomarkers as clinical utility but also on the cost-effectiveness of those biomarkers. Genetic biomarkers in OSCC are in progress, and results have been promising but limited in their effectiveness. Current opportunities and challenges for molecular targeting for OHNSCC have been discussed. Survival analyses indicated that NKX3-1 loss is a significant risk factor to decrease the disease-free survival and the overall survival rates. This is the first time that the significant association of NKX3-1 loss and occult LNM was indicated in OSCC. Loss of NKX3-1 may be a potential biomarker for occult LNM of OSCC. Polymorphism of rs174549 (FADS1) is an independent favorable factor in predicting prognosis of oral cancer patients who undergo chemoradiotherapy and is a potential biomarker for personalize treatment in the future. Genetic biomarkers including Notch1 signaling pathway related with OSSC were reviewed and discussed in detail.,
| Conclusion and Future Perspectives|| |
In conclusion, up-to-date molecular epidemiology studies of OSCC have recently included more studies of biomarkers. However, fewer biomarkers were valuable in diagnosis, treatment, and prognosis prediction. Larger population-based and well-designed molecular epidemiology studies are needed to confirm results. Molecular epidemiology study paradigms should be carried out, combining the frameworks of epidemiology methods and OSCC biomarkers. In the era of precision medicine, OSCC biomarkers will reach a new level of complexity. This increasing complexity will require rigorous approaches to study design, analysis, and interpretation.
Molecular epidemiological studies of OSCC have explored the genomic variants affecting signaling, epigenetic regulation, RNAs, proteins, and pathways involved in cell proliferation or invasion., However, much work remains to be done including identifying biomarkers for screening, efficacy evaluation, and prognosis prediction. In the future, more and more molecular epidemiological studies will take advantage of population-based, larger sample-size GWAS, and more evidence-based biomarkers will be identified for precision medicine.
Financial support and sponsorship
This study was financially supported by National Natural Science Foundation of China (81072353) and the social development project in Shaanxi province (2016SF-086).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Konduru R, Newtonraj A, Arun S, Velavan A, Singh Z. Oral cancer awareness of the general public in coastal village areas of Tamil Nadu, India: a population based cross sectional study. Int J Commun Med Public Health
2016; 3 (7): 1932–9.
Johnson S, McDonald JT, Corsten M. Oral cancer screening and socioeconomic status. J Otolaryngol Head Neck Surg
2012; 41 (2): 102–7.
International Agency for Research on Cancer. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide. International Agency for Research on Cancer; 2012. Available from: http://www.globocan.iarc.fr/Default.aspx
. [Last accessed on 2017 Jul 28].
Bray F, Ren JS, Masuyer E, Ferlay J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer
2013; 132 (5): 1133–45.
Salahshourifar I, Vincent-Chong VK, Kallarakkal TG, Zain RB. Genomic DNA copy number alterations from precursor oral lesions to oral squamous cell carcinoma. Oral Oncol
2014; 50 (5): 404–12.
Jithesh PV, Risk JM, Schache AG, Dhanda J, Lane B, Liloglou T, Shaw RJ. The epigenetic landscape of oral squamous cell carcinoma. Br J Cancer
2013; 108 (2): 370–9.
Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, Møller B, Pukkala E, Schiller JT, Youngman L, Lehtinen M, Dillner J. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med
2001; 344 (15): 1125–31.
Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Curado MP, Ferlay J, Franceschi S, Rosenberg PS, Bray F, Gillison ML. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol
2013; 31 (36): 4550–9.
Lam JO, Lim WY, Chow KY, D'Souza G. Incidence, trends and ethnic differences of oropharyngeal, anal and cervical cancers: Singapore, 1968-2012. PLoS One
2015; 10 (12): e0146185.
Thomas SJ, Bain CJ, Battistutta D, Ness AR, Paissat D, Maclennan R. Betel quid not containing tobacco and oral cancer: a report on a case-control study in Papua New Guinea and a meta-analysis of current evidence. Int J Cancer
2007; 120 (6): 1318–23.
Boonkitticharoen V, Kulapaditharom B, Leopairut J, Kraiphibul P, Larbcharoensub N, Cheewaruangroj W, Chintrakarn C, Pochanukul L. Vascular endothelial growth factor a and proliferation marker in prediction of lymph node metastasis in oral and pharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg
2008; 134 (12): 1305–11.
Eleftheriadou A, Chalastras T, Ferekidou E, Yiotakis I, Kyriou L, Tzagarakis M, Ferekidis E, Kandiloros D. Association between squamous cell carcinoma of the head and neck and serum folate and homocysteine. Anticancer Res
2006; 26 (3B): 2345–8.
Liu SZ, Zandberg DP, Schumaker LM, Papadimitriou JC, Cullen KJ. Correlation of p16 expression and HPV type with survival in oropharyngeal squamous cell cancer. Oral Oncol
2015; 51 (9): 862–9.
Hennessey PT, Westra WH, Califano JA. Human papillomavirus and head and neck squamous cell carcinoma: recent evidence and clinical implications. J Dent Res
2009; 88 (4): 300–6.
Khan Z, Tönnies J, Müller S. Smokeless tobacco and oral cancer in South Asia: a systematic review with meta-analysis. J Cancer Epidemiol
2014; 2014: 394696.
Khoury MJ, Dorman JS. The human genome epidemiology network. Am J Epidemiol 1998; 148 (1): 1–3.
Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med
2015; 372 (9): 793–5.
Furberg AH, Ambrosone CB. Molecular epidemiology, biomarkers and cancer prevention. TRENDS in molecular medicine. Trends Mol Med
2001; 7 (11): 517–21.
Henry N, Hayes DF. Cancer biomarkers. Mol Oncol
2012; 6 (2): 140–6.
Mishra A, Verma M. Cancer biomarkers: are we ready for the prime time? Cancers (Basel)
2010; 2 (1): 190–208.
Ballman KV. Biomarker: predictive or prognostic? J Clin Oncol
2015; 33 (33): 3968–71.
Sinevici N, O'sullivan J. Oral cancer: deregulated molecular events and their use as biomarkers. Oral Oncol
2016; 61: 12–8.
Al-Swiahb JN, Chen CH, Chuang HC, Fang FM, Tasi HT, Chien CY. Clinical, pathological and molecular determinants in squamous cell carcinoma of the oral cavity. Future Oncol
2010; 6 (5): 837–50.
Pérez-Sayáns M, Somoza-Martín JM, Barros-Angueira F, Reboiras-López MD, Gándara Rey JM, García-García A. Genetic and molecular alterations associated with oral squamous cell cancer (Review). Oncol Rep
2009; 22 (6): 1277–82.
Tanaka T, Tanaka M, Tanaka T. Oral carcinogenesis and oral cancer chemoprevention: a review. Patholog Res Int
2011; 2011: 431246.
Carlson CS, Eberle MA, Kruglyak L, Nickerson DA. Mapping complex disease loci in whole-genome association studies. Nature
2004; 429 (6990): 446–52.
Lesseur C, Diergaarde B, Olshan AF, Wünsch-Filho V, Ness AR, Liu G, Lacko M, Eluf-Neto J, Franceschi S, Lagiou P, Macfarlane GJ, Richiardi L, Boccia S, Polesel J, Kjaerheim K, Zaridze D, Johansson M, Menezes AM, Curado MP, Robinson M, Ahrens W, Canova C, Znaor A, Castellsagué X, Conway DI, Holcátová I, Mates D, Vilensky M, Healy CM, Szeszenia-Dąbrowska N, Fabiánová E, Lissowska J, Grandis JR, Weissler MC, Tajara EH, Nunes FD, de Carvalho MB, Thomas S, Hung RJ, Peters WH, Herrero R, Cadoni G, Bueno-de-Mesquita HB, Steffen A, Agudo A, Shangina O, Xiao X, Gaborieau V, Chabrier A, Anantharaman D, Boffetta P, Amos CI, McKay JD, Brennan P. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat Genet
2016; 48 (12): 1544–50.
Xu L, Tang H, Chen DW, El-Naggar AK, Wei P, Sturgis EM. Genome-wide association study identifies common genetic variants associated with salivary gland carcinoma and its subtypes. Cancer
2015; 121 (14): 2367–74.
Sun W, Lv W, Lv H, Zhang R, Jiang Y. Genome-wide haplotype association analysis identifies SERPINB9, SERPINE2, GAK, and HSP90B1 as novel risk genes for oral squamous cell carcinoma. Tumour Biol
2016; 37 (2): 1845–51.
Vincent-Chong VK, Anwar A, Karen-Ng LP, Cheong SC, Yang YH, Pradeep PJ, Rahman ZA, Ismail SM, Zaini ZM, Prepageran N, Kallarakkal TG, Ramanathan A, Mohayadi NA, Rosli NS, Mustafa WM, Abraham MT, Tay KK, Zain RB. Genome wide analysis of chromosomal alterations in oral squamous cell carcinomas revealed over expression of MGAM and ADAM9. PLoS One
2013; 8 (2): e54705.
Basu B, Chakraborty J, Chandra A, Katarkar A, Baldevbhai JR, Dhar Chowdhury D, Ray JG, Chaudhuri K, Chatterjee R. Genome-wide DNA methylation profile identified a unique set of differentially methylated immune genes in oral squamous cell carcinoma patients in India. Clin Epigenetics
2017; 9: 13.
Liang YJ, Lao XM, Liang LZ, Liao GQ. Genome-wide analysis of cancer cell-derived Foxp3 target genes in human tongue squamous cell carcinoma cells. Int J Oncol
2015; 46 (5): 1935–43.
Zhang S, Feng XL, Shi L, Gong CJ, He ZJ, Wu HJ, Ling TY. Genome-wide analysis of DNA methylation in tongue squamous cell carcinoma. Oncol Rep
2013; 29 (5): 1819–26.
Chen F, He B, Yan L, Qiu Y, Lin L, Cai L. FADS1 rs174549 polymorphism may predict a favorable response to chemoradiotherapy in oral cancer patients. J Oral Maxillofac Surg
2017; 75 (1): 214–20.
Bhatnagar R, Dabholkar J, Saranath D. Genome-wide disease association study in chewing tobacco associated oral cancers. Oral Oncol
2012; 48 (9): 831–5.
Marques CF, Koifman S, Koifman RJ, Boffetta P, Brennan P, Hatagima A. Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility: results from a case-control study in Rio de Janeiro. Oral Oncol
2006; 42 (6): 632–7.
Anantharaman D, Samant TA, Sen S, Mahimkar MB. Polymorphisms in tobacco metabolism and DNA repair genes modulate oral precancer and cancer risk. Oral Oncol
2011; 47 (9): 866–72.
Olivieri EH, da Silva SD, Mendonça FF, Urata YN, Vidal DO, Faria Mde A, Nishimoto IN, Rainho CA, Kowalski LP, Rogatto SR. CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients. Oral Oncol
2009; 45 (9): e73–9.
Solomon PR, Selvam GS, Shanmugam G. Polymorphism in ADH and MTHFR genes in oral squamous cell carcinoma of Indians. Oral Dis
2008; 14 (7): 633–9.
Kietthubthew S, Sriplung H, Au WW, Ishida T. Polymorphism in DNA repair genes and oral squamous cell carcinoma in Thailand. Int J Hyg Environ Health
2006; 209 (1): 21–9.
Yete S, Pradhan S, Saranath D. Single nucleotide polymorphisms in an Indian cohort and association of CNTN4, MMP2 and SNTB1 variants with oral cancer. Cancer Genet
2017; 214–215: 16–25.
de Barros Gallo C, Marichalar-Mendia X, Setien-Olarra A, Acha-Sagredo A, Bediaga NG, Gainza-Cirauqui ML, Sugaya NN, Aguirre-Urizar JM. Toll-like receptor 2 rs4696480 polymorphism and risk of oral cancer and oral potentially malignant disorder. Arch Oral Biol
2017; 82: 109–14.
Jia G, Wang X, Yan M, Chen W, Zhang P. CD166-mediated epidermal growth factor receptor phosphorylation promotes the growth of oral squamous cell carcinoma. Arch Oral Biol
2017; 82: 109–14.
Kietthubthew S, Wickliffe J, Sriplung H, Ishida T, Chonmaitree T, Au WW. Association of polymorphisms in proinflammatory cytokine genes with the development of oral cancer in Southern Thailand. Int J Hyg Environ Health
2010; 213 (2): 146–52.
Ma L, Chen J, Song X, Yuan H, Wang Y, Wu Y, Wang Z. Evidence that the genetic polymorphism rs1412115 on chromosome 10 is associated with risk for oral squamous cell carcinoma. Gene
2015; 560 (2): 137–9.
Metzger CS, Kämmerer PW, Schmidtmann I, Brieger J. Vascular endothelial growth factor polymorphisms as effect modifiers of oral squamous cell carcinoma risk: a systematic review and meta-analysis. Mol Clin Oncol
2015; 3 (2): 347–52.
Padhi SS, Roy S, Kar M, Saha A, Roy S, Adhy A, Baisakh M, Banerjee B. Role of CDKN2A/p16 expression in the prognostication of oral squamous cell carcinoma. Oral Oncol
2017; 73: 27–35.
Chawla JP, Iyer N, Soodan KS, Sharma A, Khurana SK, Priyadarshni P. Role of miRNA in cancer diagnosis, prognosis, therapy and regulation of its expression by Epstein-Barr virus and human papillomaviruses: with special reference to oral cancer. Oral Oncol
2015; 51 (8): 731–7.
Momen-Heravi F, Trachtenberg AJ, Kuo WP, Cheng YS. Genomewide study of salivary microRNAs for detection of oral cancer. J Dent Res
2014; 93(7 Suppl): 86S–93S.
Troiano G, Boldrup L, Ardito F, Gu X, Lo Muzio L, Nylander K. Circulating miRNAs from blood, plasma or serum as promising clinical biomarkers in oral squamous cell carcinoma: a systematic review of current findings. Oral Oncol
2016; 63: 30–7.
Min A, Zhu C, Peng S, Rajthala S, Costea DE, Sapkota D. MicroRNAs as important players and biomarkers in oral carcinogenesis. Biomed Res Int
2015; 2015: 186904.
Li S, Chen X, Liu X, Yu Y, Pan H, Haak H, Schmidt J, Ziebolz D, Schmalz G. Complex integrated analysis of lncRNAs-miRNAs-mRNAs in oral squamous cell carcinoma. Oral Oncol
2017; 73: 1–9.
González-Ramírez I, Soto-Reyes E, Sánchez-Pérez Y, Herrera LA, García-Cuellar C. Histones and long non-coding RNAs: the new insights of epigenetic deregulation involved in oral cancer. Oral Oncol
2014; 50 (8): 691–5.
García MP, García-García A. Epigenome and DNA methylation in oral squamous cell carcinoma. Methods Mol Biol
2012; 863: 207–19.
Mascolo M, Siano M, Ilardi G, Russo D, Merolla F, De Rosa G, Staibano S. Epigenetic disregulation in oral cancer. Int J Mol Sci
2012; 13 (2): 2331–53.
González-Ramírez I, García-Cuellar C, Sánchez-Pérez Y, Granados-García M. DNA methylation in oral squamous cell carcinoma: molecular mechanisms and clinical implications. Oral Dis
2011; 17 (8): 771–8.
Shah FD, Begum R, Vajaria BN, Patel KR, Patel JB, Shukla SN, Patel PS. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian J Clin Biochem
2011; 26 (4): 326–34.
Panta P, Venna VR. Salivary RNA signatures in oral cancer detection. Anal Cell Pathol (Amst)
2014; 2014: 450629.
Guerra EN, Acevedo AC, Leite AF, Gozal D, Chardin H, De Luca Canto G. Diagnostic capability of salivary biomarkers in the assessment of head and neck cancer: a systematic review and meta-analysis. Oral Oncol
2015; 51 (9): 805–18.
Lim AM, Wong NC, Pidsley R, Zotenko E, Corry J, Dobrovic A, Clark SJ, Rischin D, Solomon B. Genome-scale methylation assessment did not identify prognostic biomarkers in oral tongue carcinomas. Clin Epigenetics
2016; 8: 74.
Cheng SJ, Chang CF, Lee JJ, Chen HM, Wang HJ, Liou YL, Yen C, Chiang CP. Hypermethylated ZNF582 and PAX1 are effective biomarkers for detection of oral dysplasia and oral cancer. Oral Oncol
2016; 62: 34–43.
Vincent-Chong VK, Salahshourifar I, Woo KM, Anwar A, Razali R, Gudimella R, Rahman ZA, Ismail SM, Kallarakkal TG, Ramanathan A, Wan Mustafa WM, Abraham MT, Tay KK, Zain RB. Genome wide profiling in oral squamous cell carcinoma identifies a four genetic marker signature of prognostic significance. PLoS One
2017; 12 (4): e0174865.
Adami GR, Tang JL, Markiewicz MR. Improving accuracy of RNA-based diagnosis and prognosis of oral cancer by using noninvasive methods. Oral Oncol
2017; 69: 62–7.
Rivera C, Oliveira AK, Costa RA, De Rossi T, Paes Leme AF. Prognostic biomarkers in oral squamous cell carcinoma: a systematic review. Oral Oncol
2017; 72: 38–47.
Weber M, Iliopoulos C, Moebius P, Büttner-Herold M, Amann K, Ries J, Preidl R, Neukam FW, Wehrhan F. Prognostic significance of macrophage polarization in early stage oral squamous cell carcinomas. Oral Oncol
2016; 52: 75–84.
Sedghizadeh PP, Billington WD, Paxton D, Ebeed R, Mahabady S, Clark GT, Enciso R. Is p16-positive oropharyngeal squamous cell carcinoma associated with favorable prognosis? A systematic review and meta-analysis. Oral Oncol
2016; 54: 15–27.
Kornman KS, Polverini PJ. Clinical application of genetics to guide prevention and treatment of oral diseases. Clin Genet
2014; 86 (1): 44–9.
Miyaguchi K, Uzawa N, Mogushi K, Takahashi K, Michikawa C, Nakata Y, Sumino J, Okada N, Mizushima H, Fukuoka Y, Tanaka H. Loss of NKX3-1 as a potential marker for an increased risk of occult lymph node metastasis and poor prognosis in oral squamous cell carcinoma. Int J Oncol
2012; 40 (6): 1907–14.
Ali J, Sabiha B, Jan HU, Haider SA, Khan AA, Ali SS. Genetic etiology of oral cancer. Oral Oncol
2017; 70: 23–8.
Yoshida R, Nagata M, Nakayama H, Niimori-Kita K, Hassan W, Tanaka T, Shinohara M, Ito T. The pathological significance of NOTCH1 in oral squamous cell carcinoma. Lab Invest
2013; 93 (10): 1068–81.