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. 2025 Aug 7;25(1):1274.
doi: 10.1186/s12885-025-14506-0.

Detection and significance of HPV16 E5-specific productive transcripts in oropharyngeal carcinoma

Maria Gabriella Donà  1 , Francesca Paolini  2   3   4 , Maria Benevolo  5 , Francesca Rollo  5 , Elisabetta Merenda  6 , Eugenia Giuliani  1 , Flaminia Campo  7 , Claudia Bonomo  5 , Francesco Lorusso  8 , Fabio Cecconi  9 , Rita Antonelli  10 , Ignazio La Mantia  11 , Giuseppe D'Ermo  12 , Renato Covello  5 , Barbara Pichi  7 , Raul Pellini  7 , Antonio Carlos De Freitas  13 , Andrew Sharabi  14 , Aldo Venuti  15   16
Affiliations

Detection and significance of HPV16 E5-specific productive transcripts in oropharyngeal carcinoma

Maria Gabriella Donà et al. BMC Cancer. .

Abstract

Background: HPV16 is implicated in around 30% of oropharyngeal cancers (OPCs). HPV-associated OPCs generally show a better prognosis, but 20% deviate from this trend, indicating a need for better molecular profiling. HPV16-E5 is an oncoprotein encoded by an mRNA that undergoes extensive splicing, with only one specific transcript being translatable. The prognostic significance of this E5-productive transcript in HPV-related OPCs is not well-studied.

Methods: We retrospectively analysed 74 HPV16-positive OPC cases diagnosed between 2011 and 2021. FFPE tissue samples were used for p16, EGFR, and HLA-I analysis by immunohistochemistry while E5, productive E5, E6 and E7 transcripts were detected by qPCR. Survival analysis was conducted using Kaplan-Meier curves and log-rank tests.

Results: Productive HPV16-E5 transcripts were detected in 11.3% of OPCs. There was no significant association between HPV16-E5 transcripts and EGFR or HLA-I expression. However, the presence of the productive E5 transcript was associated with worse progression-free survival (PFS) (p = 0.0024). EGFR or HLA-I expression was not significantly associated with PFS (p = 0.17 and p = 0.93, respectively).

Conclusions: This study demonstrates for the first time the presence of E5-productive transcripts in HPV16-positive OPCs and its association with poorer PFS, highlighting its potential as a prognostic marker. Further research with larger cohorts is needed to validate these findings.

Keywords: E5 mRNA; EGFR; HLA-I; HPV; Oropharyngeal cancer (OPC); PFS; Transcripts.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All enrolled patients signed an informed consent to the protocol approved by the IRCCS Regina Elena National Cancer Institute, Istituti Fisioterapici Ospitalieri, Institutional Review Board (RS 1443/20). The study was conducted in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Proportions of HPV16-associated OPC samples positive for the presence of HPV16 E5, E6, E7, and E5 productive mRNA.This figure highlights the differential expression of these viral transcripts in HPV16-positive OPCs, with the E5-specific productive mRNA being the least commonly detected
Fig. 2
Fig. 2
Immunostaining for EGFR and HLA-I in HPV16-associated OPCs. HPV16-associated tonsillar squamous cell carcinoma: A Hematoxylin and Eosin staining (H&E); B Negative EGFR staining; C Intact HLA-I expression. HPV16-associated base of the tongue squamous cell carcinoma: D H&E staining; E Positive EGFR staining; F HLA-I diffuse loss. 3′,3′ diaminobenzidine (DAB) was used as a chromogenic substrate. 200× magnification
Fig. 3
Fig. 3
Unadjusted Kaplan Meier curves illustrating progression-free survival (PFS) outcomes for the 71 HPV16-associated OPC patients with both a valid mRNA analysis and immunohistochemistry results. Patients are stratified according to the expression of a HPV16-E5 mRNA, b HPV16-E5 productive mRNA, c EGFR, and d HLA-I; p values for the log-rank test used to compare the survival curves are also reported
See this image and copyright information in PMC

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