Detection of High-Risk Human Papillomavirus in Oral Cavity Squamous Cell Carcinoma Using Multiple Analytes and Their Role in Patient Survival

Abstract

Purpose Accurate detection of human papillomavirus (HPV) in oral cavity squamous cell carcinoma (OSCC) is essential to understanding the role of HPV in disease prognosis and management of patients. We used different analytes and methods to understand the true prevalence of HPV in a cohort of patients with OSCC with different molecular backgrounds, and we correlated HPV data with patient survival. Methods We integrated data from multiple analytes (HPV DNA, HPV RNA, and p16), assays (immunohistochemistry, polymerase chain reaction [PCR], quantitative PCR [qPCR], and digital PCR), and molecular changes (somatic mutations and DNA methylation) from 153 patients with OSCC to correlate p16 expression, HPV DNA, and HPV RNA with HPV incidence and patient survival. Results High prevalence (33% to 58%) of HPV16/18 DNA did not correlate with the presence of transcriptionally active viral genomes (15%) in tumors. Eighteen percent of the tumors were p16 positive and only 6% were both HPV DNA and HPV RNA positive. Most tumors with relatively high copy number HPV DNA and/or HPV RNA, but not with HPV DNA alone (irrespective of copy number), were wild-type for TP53 and CASP8 genes. In our study, p16 protein, HPV DNA, and HPV RNA, either alone or in combination, did not correlate with patient survival. Nine HPV-associated genes stratified the virus-positive from the virus-negative tumor group with high confidence ( P < .008) when HPV DNA copy number and/or HPV RNA were considered to define HPV positivity, and not HPV DNA alone, irrespective of copy number ( P < .2). Conclusion In OSCC, the presence of both HPV RNA and p16 is rare. HPV DNA alone is not an accurate measure of HPV positivity and therefore may not be informative. HPV DNA, HPV RNA, and p16 do not correlate with patients’ outcome.

Diagnostic and prognostic impact of E6/E7 mRNA compared to HPV DNA and p16 expression in head and neck cancers: an Egyptian study

“…In the current study, two of the HPV DNA-negative samples revealed positive HPV16 viral transcripts. A previous study by Palve et al [52] also found three cases with HPV E6/E7 RNA and negative HPV DNA results. This was justified by the possibility that the DNA in such tumors was degenerated and hence could not act as a proper template for DNAdependent tests.…”

The mutational landscape of early‐ and typical‐onset oral tongue squamous cell carcinoma

“…Although HPV‐positive OPSCC shares similarities with early‐onset OTSCC in terms of the overall mutation rate, HPV‐positive OPSCC specimens tend to have infrequent TP53 or CDKN2A mutations 27 . Several studies have looked for possible involvement of HPV in OTSCC, but results have shown that only approximately 5% of OTSCC specimens have detectable HPV 9,41,42 . In addition, broader transcriptome searches for other possible viruses have yet to yield any substantive results 9 .…”

“…27 Several studies have looked for possible involvement of HPV in OTSCC, but results have shown that only approximately 5% of OTSCC specimens have detectable HPV. 9,41,42 In addition, broader transcriptome searches for other possible viruses have yet to yield any substantive results. 9 Thus, the underlying cause for the rise in early OTSCC remains enigmatic.…”

Functional genomics screen with pooled shRNA library and gene expression profiling with extracts of Azadirachta indica identify potential pathways for therapeutic targets in head and neck squamous cell carcinoma

“…Inhibitors targeting epidermal growth factor receptor (EGFR)-regulated pathways, Vascular endothelial growth factor (VEGF) pathway, multiple kinases, PI3-K/AKT/mTOR pathway, and other novel targets, in a combined modality treatment with immunotherapy, are likely to increase therapeutic efficacy in patients with HNSCC (Matta & Ralhan, 2009; Kaidar-Person, Gil & Billan, 2018). Except for oropharyngeal tumors, human papillomavirus (HPV) is rare in oral cavity tumors (Palve et al, 2018). Its role in risk stratification is still under clinical trial evaluations in non-oropharyngeal tumors.…”