Molecular insight into Proliferative Verrucous Leukoplakia: Are TERT promoter mutations a predictive marker?

Proliferative verrucous leukoplakia (PVL) is a rare yet aggressive oral potentially malignant disease (OPMD) with the greatest rate of malignant transformation. Its pathophysiology is poorly understood despite much histopathological and molecular research. Particularly, Telomerase reverse transcriptase (TERT) promoter mutations at C228T and C250T have been linked to many epithelial malignancies; however, their significance in PVL is yet unknown in the Indian population. The aim of this study was to assess frequency of TERT promoter mutations (C228T, C250T) and rs2853669 single nucleotide polymorphism (SNP) in PVL, oral leukoplakia (OL), oral squamous cell carcinoma (OSCC) and healthy controls. 120 fresh frozen tissue specimens (30 each of OL, PVL, OSCC and controls) were tested for presence of C228T and C250T mutation in TERT promoter gene region and SNP at rs2853669, using Sanger sequencing on genomic DNA. TERT C228T mutation was found in 6.7%, 0% and 20% cases in PVL, OL and OSCC group (p = 0.03) respectively. TERT C250T mutation was present only in OSCC group (6.7% cases). None of the two mutations were present in controls. Both the mutations were mutually exclusive of each other. A significant association was found between rs2853669 SNP and epithelial dysplasia in OL, specifically with CC genotype (p = 0.04). Molecular signature of PVL shows limited evidence of TERT promoter mutations. The findings of this study suggest that the genetic underpinnings of PVL are distinct from those commonly observed in other forms of cancerous lesions.