Oral cancers preceded by proliferative verrucous leukoplakia exhibit distinctive molecular features.

Objective: Proliferative verrucous leukoplakia (PVL) has high rates of malignant transformation into oral squamous cell carcinoma (OSCC), but the clinical and evolutionary pattern of OSCC from PVL (PVL‐OSCC) is more favorable than that of OSCC not preceded by PVL (OSCC). Here, we aimed to explore the pathophysiologic differences between PVL‐OSCC and OSCC through transcriptomic and DNA methylation analyses. Materials and methods: In this case‐control study, oral biopsies from 8 PVL‐OSCC and 10 OSCC patients were obtained for global sequencing using RNAseq and a genome‐wide DNA methylation analysis via the Infinium EPIC Platform (graphical abstract). Results: One hundred and thirty‐three differentially expressed genes (DEGs) were detected, 94 of them upregulated in OSCC. Most of these genes were previously described in cancer and associated with prognosis. The integrative analysis revealed 26 DEGs, corresponding to 37 CpGs, whose promoters were regulated by DNA methylation. Twenty‐nine of the CpGs were found as hypermethylated in PVL‐OSCC. Only 5 of the genes that were aberrantly methylated and differentially expressed were upregulated in PVL‐OSCC patients, whereas 21 were underexpressed. Conclusions: PVL‐OSCC patients presented lower expression of cancer‐related genes. Hypermethylation of the promoter region of many genes was also noticed, indicating that DNA methylation could be a regulatory mechanism. [ABSTRACT FROM AUTHOR]