A novel genomic signature reclassifies an oral cancer subtype

Verrucous carcinoma of the oral cavity (OVC) is considered a subtype of classical oral squamous cell carcinoma (OSCC). Diagnosis is problematic, and additional biomarkers are needed to better stratify patients. To investigate their molecular signature, we performed low‐coverage copy number (CN) sequencing on 57 OVC and exome and RNA sequencing on a subset of these and compared the data to the same OSCC parameters. CN results showed that OVC lacked any of the classical OSCC patterns such as gain of 3q and loss of 3p and demonstrated considerably fewer genomic rearrangements compared to the OSCC cohort. OVC and OSCC samples could be clearly differentiated. Exome sequencing showed that OVC samples lacked mutations in genes commonly associated with OSCC (TP53, NOTCH1, NOTCH2, CDKN2A and FAT1). RNA sequencing identified genes that were differentially expressed between the groups. In silico functional analysis showed that the mutated and differentially expressed genes in OVC samples were involved in cell adhesion and keratinocyte proliferation, while those in the OSCC cohort were enriched for cell death and apoptosis pathways. This is the largest and most detailed genomic and transcriptomic analysis yet performed on this tumour type, which, as an example of non‐metastatic cancer, may shed light on the nature of metastases. These three independent investigations consistently show substantial differences between the cohorts. Taken together, they lead to the conclusion that OVC is not a subtype of OSCC, but should be classified as a distinct entity. What's new? Oral verrucous carcinoma (OVC) is considered to be a variant of oral squamous cell carcinoma (OSCC), due mainly to similarities in appearance. However, observed differences in growth patterns and metastatic behavior have raised questions about their classification. Here, comparisons of genomic data derived from copy number sequencing, exome sequencing, and RNA sequencing indicate that OVC is distinct from its squamous cell counterpart. In particular, OVCs were characterized by fewer genomic changes than OSCCs, and the two lacked common driver events. The unique genomic features of OVC warrant its reclassification within the oral cancer taxonomy.