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      Identification of a combined biomarker for malignant transformation in oral submucous fibrosis

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          Abstract

          Background

          Oral submucous fibrosis ( OSF) is a chronic progressive disease of the oral cavity that is considered a common potentially malignant disorder in South Asia. Areca nut chewing is the main etiological factor, but its carcinogenic mechanism has yet to be proven. The purpose of this study was to identify the useful biomarkers in predicting high‐risk patients with OSF.

          Methods

          Thirty‐six cases of OSF and six cases of normal oral mucosa ( NOM) were used for this study. Immunohistochemical staining was performed for Ki67, cyclin D1, p16, p53, β‐catenin, c‐Jun, c‐Met, and insulin‐like growth factor II mRNA‐binding protein 3 ( IMP3). The expression patterns of NOM served as guidelines for the scoring system.

          Results

          The expression of Ki67, cyclin D1, c‐Met, IMP3, and β‐catenin showed a significant difference between OSF and NOM samples. The combined biomarkers of Ki67 and p16 showed significantly different expression between the transformation and non‐transformation groups. With discriminant analysis, we proposed a noble formula and cutoff value for predicting high‐risk patients with OSF.

          Conclusion

          The notable biomarkers in our present study were Ki67 and p16 showing significantly different expression levels between the transformation and non‐transformation groups. With the identification of high‐risk patients with OSF, we can expect to develop more intensive treatment modalities, leading to the reduction in cancer transformation rate from OSF.

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          Most cited references24

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          Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: a review of agents and causative mechanisms.

          In south-east Asia, Taiwan and Papua New Guinea, smoking, alcohol consumption and chewing of betel quid with or without tobacco or areca nut with or without tobacco are the predominant causes of oral cancer. In most areas, betel quid consists of a mixture of areca nut, slaked lime, catechu and several condiments according to taste, wrapped in a betel leaf. Almost all habitual chewers use tobacco with or without the betel quid. In the last few decades, small, attractive and inexpensive sachets of betel quid substitutes have become widely available. Aggressively advertised and marketed, often claimed to be safer products, they are consumed by the very young and old alike, particularly in India, but also among migrant populations from these areas world wide. The product is basically a flavoured and sweetened dry mixture of areca nut, catechu and slaked lime with tobacco (gutkha) or without tobacco (pan masala). These products have been strongly implicated in the recent increase in the incidence of oral submucous fibrosis, especially in the very young, even after a short period of use. This precancerous lesion, which has a high rate of malignant transformation, is extremely debilitating and has no known cure. The use of tobacco with lime, betel quid with tobacco, betel quid without tobacco and areca nut have been classified as carcinogenic to humans. As gutkha and pan masala are mixtures of several of these ingredients, their carcinogenic affect can be surmised. We review evidence that strongly supports causative mechanisms for genotoxicity and carcinogenicity of these substitute products. Although some recent curbs have been put on the manufacture and sale of these products, urgent action is needed to permanently ban gutkha and pan masala, together with the other established oral cancer-causing tobacco products. Further, education to reduce or eliminate home-made preparations needs to be accelerated.
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            Potentially malignant disorders of the oral cavity: current practice and future directions in the clinic and laboratory.

            Despite commendable progress in the prevention, detection, and treatment of a wide variety of solid tumor types, oral squamous cell carcinoma (OSCC) remains a significant health burden across the globe. OSCC carcinogenesis involves accumulation of genetic alterations that coincide with the multistep malignant transformation of normal oral epithelium. OSCC is often first diagnosed at late stages of the disease (advanced regional disease and/or metastasis). Delayed diagnosis precludes successful treatment and favorable outcomes. In clinical practice, opportunities exist to identify patients with oral potentially malignant disorders (OPMDs), which precede the development of cancer. This review addresses the current status of laboratory and clinical research on OPMDs, with emphasis on leukoplakia and erythroplakia. OSF is also presented, though there is a paucity of published studies on this disorder. We focus on findings that could translate into earlier diagnosis and more efficacious treatment of those lesions with significant malignant potential. We explore how markers of OPMD malignant transformation might be implemented into current diagnostic practice to help clinicians objectively stratify patients into treatment/follow-up groups according to relative risk. We provide an overview of recently concluded and ongoing OPMD chemoprevention trials. We describe laboratory OPMD models that can be used to not only to reveal the genetic and molecular intricacies of oral cancer but also to develop novel screening methods and therapeutic approaches. Finally, we call for targeted screening programs of at-risk populations in order to facilitate diagnosis and treatment of OPMD and early OSCC. © 2014 UICC.
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              Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.

              Many tumour types have been reported to have deletion of 9p21 (refs 1-6). A candidate target suppressor gene, p16 (p16INK4a/MTS-1/CDKN2), was recently identified within the commonly deleted region in tumour cell lines. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletion and the importance of p16 in primary tumours. We tested 545 primary tumours by microsatellite analysis with existing and newly cloned markers around the p16 locus. We have now found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer. Moreover, fine mapping of these deletions implicates a 170 kb minimal region that includes p16 and excludes p15.
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                Author and article information

                Contributors
                wmtilak@pdn.ac.lk
                jink@yuhs.ac
                Journal
                J Oral Pathol Med
                J. Oral Pathol. Med
                10.1111/(ISSN)1600-0714
                JOP
                Journal of Oral Pathology & Medicine
                John Wiley and Sons Inc. (Hoboken )
                0904-2512
                1600-0714
                06 August 2016
                July 2017
                : 46
                : 6 ( doiID: 10.1111/jop.2017.46.issue-6 )
                : 431-438
                Affiliations
                [ 1 ] Department of Oral Pathology Oral Cancer Research Institute Yonsei University College of Dentistry Seoul South Korea
                [ 2 ] Dental School Mongolian National University of Medical Science Ulaanbaatar Mongolia
                [ 3 ] Department of Pathology Yanbian University Hospital Yanji China
                [ 4 ] Brain Korea 21 Plus Project Yonsei University College of Dentistry Seoul South Korea
                [ 5 ] Department of Medical Laboratory Science Faculty of Allied Health Sciences University of Peradeniya Peradeniya Sri Lanka
                [ 6 ] Department of Oral Medicine & Periodontology Faculty of Dental Sciences University of Peradeniya Peradeniya Sri Lanka
                [ 7 ] Department of Oral Pathology Faculty of Dental Sciences University of Peradeniya Peradeniya Sri Lanka
                Author notes
                [*] [* ] Correspondence: Jin Kim, Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 120‐752, Korea. Tel: +82 2 2228 3031, Fax: +82 2 392 2959, E‐mail: jink@ 123456yuhs.ac

                and

                Wanninayake M Tilakaratne, Department of Oral Pathology, Peradeniya University Faculty of Dentistry, Peradeniya 20400, Sri Lanka. Tel: +94 812397201, Fax: +94 812388948, E‐mail: wmtilak@ 123456pdn.ac.lk

                [†]

                These authors equally contributed to this work.

                Article
                JOP12483
                10.1111/jop.12483
                5516200
                27497264
                b8a03dca-e442-4a3a-85ab-0583defde8b5
                © 2016 The Authors. Journal of Oral Pathology & Medicine Published by John Wiley & Sons Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 14 July 2016
                Page count
                Figures: 3, Tables: 3, Pages: 8, Words: 5347
                Funding
                Funded by: Ministry of Sciences, ICT, and Future plan
                Award ID: 2013K1A3A9A01044071
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jop12483
                July 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:19.07.2017

                combined biomarkers,oral submucous fibrosis,risk assessment,squamous cell carcinoma

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