A novel genomic signature reclassifies an oral cancer subtype

Abstract

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.

Oral epithelial dysplasia: Recognition, grading and clinical significance

“…The disconnect between dysplastic features and behaviour is shared with verrucous carcinoma which has a distinct molecular signature (Samman et al, 2015) probably shared with verrucous dysplasia, and possibly distinct from other dysplastic lesions (Okoturo et al, 2018).…”

“…No standardised criteria exist for the histopathological diagnosis of PVL and the clinical features remain paramount for establishing the diagnosis, particularly a predilection for palatal and gingival mucosa, older female patients and lack of association with risk factors. Whether there is a clear molecular distinction between PVL and other OPMDs with dysplasia remains unclear, though numerous differences are identified (Okoturo et al, 2018) and a distinct molecular signature is proposed for verrucous carcinoma (Samman et al, 2015).…”

Oral verrucous carcinoma: From multifactorial etiology to diverse treatment regimens (Review)

“…Genetic alterations are involved in polymorphism, point mutation, deletion, and other alterations. Previous investigation mainly focused on gene profiling (47,48).…”

The Akt/mTOR pathway is activated in verrucous carcinoma of the oral cavity

“…Moreover, copy number and exome sequencing showed that OVC lacked classical OSCC patterns (e.g., gain of 3q and loss of 3p) and exhibited fewer genomic rearrangements compared to OSCC. Additionally, OVC samples lacked mutations in genes commonly associated with OSCC (TP53, NOTCH1, NOTCH2, CDKN2A, and FAT1) . Here, we compared for the first time in the literature the expression of the components of the Akt/mTOR pathway between OSCC and OVC.…”