Multi-regional molecular genomic profiling to identify the drivers of oral field cancerization

Normal oral epithelium acquires genomic alterations when exposed to carcinogens, some of which affect expressions of genes, and results in tissue dysplasia. Subsequent clonal expansion of dysplastic cells gives rise to oral tumors. Often multifocal precancerous and malignant lesions arise within the oral cavity from a “field” of epithelial cells. The presence of spatially distributed lesions in the oral cavity may lead to post-surgical local recurrence. In this study, we have performed multi-omics profiling of five malignant lesions and blood from a single patient with oral squamous cell carcinoma of the gingivobuccal region (OSCC-GB) with field cancerization. A missense protease domain mutation in CASP8 was common among the five malignant lesions in the same oral cavity, although with different variant allele frequencies. In these lesions, other molecular events – different mutations in OSCC driver genes (such as, PIK3CA, FBXW7), somatic mutational signatures, specific arm-level copy number alterations etc. – were observed. These features indicate that the CASP8 protease domain mutation is the earliest molecular event in a “field” of cells that are primed for malignant transformation followed by other molecular alterations. These findings provide us the confidence that CASP8 alterations are early events in tumorigenesis.