Examining the contribution of smoking and HPV towards the etiology of oral cavity squamous cell carcinoma using high-throughput sequencing: A prospective observational study

Abstract

Oral cavity Squamous Cell Carcinoma (OCSCC) is a common form of head and neck cancer throughout the developed and developing world. However, the etiology of OCSCC is still unclear.Here, we explored the extent to which tobacco use, Human Papillomavirus (HPV) infection and genetic and transcriptomic changes contributed to the oncogenesis of OCSCC. In a prospective observational study, we analysed fresh tissue biopsies from 45 OCSCC collected from 51 subjects presenting with OCSCC to the Brisbane Head and Neck Clinics between 2013 and 2015. Exploration of the genetic and transcriptomic landscape of the biopsies were performed using RNA sequencing (RNA-seq) and whole exome sequencing. HPV associated tumours were determined using p16 staining of histological sections and RNA sequencing. Patient demographics including tumor location within the oral cavity, and history of tobacco and alcohol use were correlated with genomic and transcriptomics analyses. About 4.5% of OCSCC were HPV associated. The most frequent mutations in the OCSCC samples were in the TP53 and CDKN2A genes, but no association of specific mutations with HPV or tobacco use was observed. Using weighted gene co-expression network analysis to explore the RNA-seq data, tumors from participants with a history of tobacco use showed a significant trend towards increased mammalian target of Rapamycin (mTOR) signaling and decreased mitochondrial respiration. In conclusion, HPV was shown to be an uncommon association with OCSCC and changes in TP53 transcriptional regulation, mTOR signaling and mitochondrial function were associated with a history of tobacco use. Larger data sets will be required to enable detection of differences which may help with development of personalized therapeutics in the future.

Oral HPV16 Prevalence in Oral Potentially Malignant Disorders and Oral Cavity Cancers

“…This is further supported by previous reports of no statistically significant differences in prognostic and survival outcomes between HPV-negative and -positive patients with non-OPC conditions, including OC [52][53][54]. Indeed, a recent study demonstrated that HPV is uncommonly associated with the oncogenesis of OC [55]. Furthermore, both HPV16-positive OPMD and OC had similar viral loads.…”

Evaluation of HPV and EBV in OSCC and the expression of p53, p16, E‐cadherin, COX‐2, MYC, and MLH1

“…genes, but no association of specific mutations with HPV (Zammit et al, 2018). In other study investigating TP53 exon 8 mutation, the frequency of mutation was significantly higher in OSCC than in controls, however, with no significant relationship between HPV infection and mutation, which may indicate that HPV infection may not strongly affect the frequency of TP53 codon 282 mutation in OSCC (Ekalaksananan et al, 2020).…”

“…(2016) argue that HPV‐negative OSCCs are significantly more likely to have mutant p53 than HPV‐positive OSCC. Accordingly, in a whole‐exome sequencing study with OSCC samples, the most frequent mutations were in the TP53 and CDKN2A genes, but no association of specific mutations with HPV (Zammit et al., 2018). In other study investigating TP53 exon 8 mutation, the frequency of mutation was significantly higher in OSCC than in controls, however, with no significant relationship between HPV infection and mutation, which may indicate that HPV infection may not strongly affect the frequency of TP53 codon 282 mutation in OSCC (Ekalaksananan et al., 2020).…”

Research progress and application of single-cell sequencing in head and neck malignant tumors

“…The inactivation of p53 plays an important role in the occurrence of HPV positive OCSCC, making it widely studied as a diagnostic gene for HPV positive OCSCC. The most common mutation in OCSCC is the TP53 gene [ 43 ]. The deregulation of p53, a tumor suppressor encoded by TP53, is a very important event in the progression of OCSCC, which leads to cell cycle hyperactivation and causes cancer events [ 44 ].…”