Genome-wide characterization of the mutational landscape of proliferative verrucous leukoplakia.

Objectives: Proliferative verrucous leukoplakia (PVL) is a rare but highly aggressive variant of oral leukoplakia that almost inevitably progresses to oral squamous cell carcinoma (OSCC). The aims of this study were to perform whole exome sequencing of a cohort of patients diagnosed with PVL and identify potential mutational profiles and pathways in this disorder.

Study Design: A total of 12 oral cavity mucosal biopsies from 6 patients with oral lesions clinically compatible with PVL were used. Of these, 9 were diagnosed as dysplasia, 1 OSCC, and 2 hyperkeratosis/hyperplasia. Exome sequencing used the Ion AmpliSeq Exome platform. Ion Reporter software was used for variant calling, annotation, and filtering. Analysis and visualization of somatic mutations was carried out using the MAFtools R package.

Results: Following exome sequencing and mutational profiling, we analyzed the profiles for cancer associated genes and signatures. Genes previously associated with OSCC, including HYDIN, MUC16, MAML3, CDKN2A, FAT1, and CASP8, were mutated in multiple samples. Several DNA damage repair genes including PARP1 were mutated in PVL samples. NOTCH and Hippo pathways were the most frequently impacted by mutation.

Conclusions: This genome wide characterization of premalignant PVL identifies both known and potentially novel oncogenic mechanisms in this disorder.