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

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Oral submucous fibrosis (OSF) is a chronic progressive oral mucosal disease with a potential for malignant transformation 1. Clinical presentation depends on the stage of the disease. Initially, most patients present with a burning sensation or intolerance to spicy food, and they may have vesicles, particularly on the palate. Ulceration and dryness of the mouth are later followed by fibrosis of the oral mucosa, leading to rigidity of the lips, tongue, and palate and causing trismus 2. The important histopathologic features consist of the deposition of dense collagen in the lamina propria associated with epithelial atrophy. Initially, there is juxta‐epithelial inflammation followed by hyalinization 3. OSF is frequently noted in South‐East Asian countries where areca nut chewing is popular, suggesting that this habit is the most important etiological factor in the pathogenesis of OSF 4.
Importantly, the malignant transformation rate was shown to be 7.6% over a period of 17 years 5. Furthermore, more than 2400 new cases of oral squamous cell carcinoma (OSCC) arising from OSF have been diagnosed each year in Taiwan due to the prevalent use of betel quid 5. Therefore, the early detection of potentially malignant OSF has been crucial in the inhibition of oral cancer.
Many efforts have been made to explore carcinogenesis and identify predictable diagnostic biomarkers in OSF. However, no useful marker has been identified to date. To identify the useful biomarkers in predicting oral cancer development in patients with OSF, we performed immunohistochemical staining for eight candidate biomarkers. Every biomarker has its own special attribution to be selected.
Ki67 and cyclin D1 can be used to evaluate the cell proliferation 7. p16 and p53 were investigated as tumor‐suppressor genes known to be affected in head‐and‐neck squamous cell carcinomas (HNSCCs). In HNSCCs, the incidence of p16 inactivation due to mutation was reported to be 10% 8 and that by homozygous deletion was 33% 9. Thus, point mutations in p53 occur in 10–17% of precancerous disease and in 35–67% of OSCC 10. To further investigate the transcriptional activity in OSF tissue, the expression levels of β‐catenin and c‐Jun were evaluated 11. Growth factor receptors c‐Met and insulin‐like growth factor II mRNA‐binding protein 3 (IMP3) were reported to play pivotal roles in tumor invasion 13.
The aim of our study was to generate a prediction model for risk assessment using combined biomarkers. Although no single biomarker has been satisfactory in predicting carcinomatous transformation of potentially malignant OSF, the combined biomarkers identified in our study may be clinically useful to detect high‐risk OSF and reduce the incidence of OSCC, thus guiding the clinician's decision on the diagnosis, treatment, and prevention strategies.

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