Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications

Abstract

Identification and management of potentially premalignant oral epithelial lesions (PPOELs) at highest risk of malignant transformation holds great promise for successful secondary prevention of oral squamous cell carcinoma, potentially reducing oral cancer morbidity and mortality. However, to date, neither clinical nor histopathologic validated risk predictors that can reliably predict which PPOELs will definitively progress to malignancy have been identified. In addition, the management of PPOELs remains a major challenge. Arguably, progress in the prevention and treatment of oral premalignancy and cancer will require improved understanding of the underlying molecular mechanisms, facilitating the discovery of diagnostic, prognostic, and predictive markers, as well as the identification of novel targeted therapeutics. This review provides a synopsis of the molecular biomarkers that have been studied in PPOELs and have been correlated with the presence and grade of dysplasia and/or their propensity to undergo malignant transformation to oral squamous cell carcinoma. The emphasis is on highlighting new emerging research fields, particularly epigenetic events, including methylation and micro-RNA regulation. Several promising biomarkers are highlighted. Current limitations and challenges are discussed. Recommendations for future focused research areas, to validate and promote clinically useful applications, are offered.

Association between p62 expression and clinicopathological characteristics in oral leukoplakia

“…Recently, molecular biology approaches have been employed to clarify the mechanism of malignant transformation and identify several risk factors of malignancy as biomarkers, but there are only a few reports concerning autophagy‐related markers (Nikitakis et al, ).…”

“…Recently, molecular biology approaches have been employed to clarify the mechanism of malignant transformation and identify several risk factors of malignancy as biomarkers, but there are only a few reports concerning autophagy-related markers (Nikitakis et al, 2018). Lévy et al (2015) analyzed the levels of p62 to investigate the status of autophagy in intestinal epithelial cells during malignant transformation in adenomatous polyposis coli.…”

“…Nagao et al (2017) studied the expression of p53 and Ki67 in response to chemoprevention of oral leukoplakia and reported that the expression of p53 is inversely associated with the clinical response to supplements administered for the condition. Studies have also reported the biomarkers involved in oral leukoplakia (Nikitakis et al, 2018), such as cornulin, keratin 4, keratin 13 (Schaaij-Visser et al, 2010), and podoplanin (de Vicente et al, 2013). Zamora et al indicated that the salivary 8-OHdG level increased in patients with chronic periodontitis and aggressive periodontitis.…”

Oral Leukoplakia: Present Views on Diagnosis, Management, Communication with Patients, and Research

“…There are many, statistically somewhat useful predictive factors of malignant transformation, such as the size of the lesion, the clinical subtype, the oral subsite, and the presence or absence of epithelial dysplasia, but these are not reliable for use in the individual patient. This also applies to the various molecular markers that have been reported in the past decades as possible predictive markers of malignant transformation [2,3]. There is an ongoing debate in the literature as whether treatment of oral leukoplakia is effective in preventing malignant transformation.…”

CDK4, CDK6, cyclin D1 and Notch1 immunocytochemical expression of oral brush liquid‐based cytology for the diagnosis of oral leukoplakia and oral cancer

“…[7][8][9][10] Recent molecular advances have revealed the multistep heterogenous nature of oral carcinogenesis that involves specific genetic and epigenetic events 11 ; however, the precise understanding of the underlying molecular mechanisms of oral carcinogenesis is still incomplete and warrant further investigations. 12 The pursuit of valid and reproducible biomarkers to predict the malignant transformation of OPMDs is still underway. 13 Nevertheless, there are several promising biomarkers that have been identified to have a role including CDK4, CDK6, cyclin D1, and Notch 1.…”