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. 2021 Jul 5;13(13):3370.
doi: 10.3390/cancers13133370.

Serum HPV16 E7 Oncoprotein Is a Recurrence Marker of Oropharyngeal Squamous Cell Carcinomas

Lucia Oton-Gonzalez  1 , John Charles Rotondo  1 , Carmen Lanzillotti  1 , Elisa Mazzoni  1 , Ilaria Bononi  2 , Maria Rosa Iaquinta  1 , Luca Cerritelli  3 , Nicola Malagutti  3 , Andrea Ciorba  3 , Chiara Bianchini  3 , Stefano Pelucchi  3 , Mauro Tognon  1 , Fernanda Martini  1
Affiliations

Serum HPV16 E7 Oncoprotein Is a Recurrence Marker of Oropharyngeal Squamous Cell Carcinomas

Lucia Oton-Gonzalez et al. Cancers (Basel). .

Abstract

Despite improved prognosis for many HPV-positive head and neck squamous cell carcinomas (HNSCCs), some cases are still marked by recurrence and metastasis. Our study aimed to identify novel biomarkers for patient stratification. Classical HPV markers: HPV-DNA, p16 and HPV mRNA expression were studied in HNSCC (n = 67) and controls (n = 58) by qPCR. Subsequently, ELISA tests were used for HPV16 L1 antibody and HPV16 E7 oncoprotein detection in serum at diagnosis and follow-up. All markers were correlated to relapse-free survival (RFS) and overall survival (OS). HPV-DNA was found in HNSCCs (29.85%), HPV16-DNA in 95% of cases, HPV16 E7 mRNA was revealed in 93.75%. p16 was overexpressed in 75% of HPV-positive HNSCC compared to negative samples and controls (p < 0.001). Classical markers correlated with improved OS (p < 0.05). Serological studies showed similar proportions of HPV16 L1 antibodies in all HNSCCs (p > 0.05). Serum E7 oncoprotein was present in 30% HPV-positive patients at diagnosis (p > 0.05) and correlated to HNSCC HPV16 E7 mRNA (p < 0.01), whereas it was associated to worse RFS and OS, especially for oropharyngeal squamous cell carcinoma (OPSCC) (p < 0.01). Detection of circulating HPV16 E7 oncoprotein at diagnosis may be useful for stratifying and monitoring HPV-positive HNSCC patients for worse prognosis, providing clinicians a tool for selecting patients for treatment de-escalation.

Keywords: E7 oncoprotein; ELISA; HPV DNA; HPV antibodies; human papillomavirus; oropharyngeal squamous cell carcinoma; patient stratification; treatment de-escalation.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Analysis of classical markers for stratification of HNSCC samples. Statistical significance was indicated as * for p < 0.05 and ** for p < 0.0001; (A) viral load quantification of HPV-positive HNSCC samples by qPCR; (B) differential p16 mRNA expression in HNSCC samples analyzed by qPCR; (C) Viral E7 mRNA expression in HPV-positive HNSCC samples; (D) Spearman correlation analyses between the expression of E7 (log2) oncogene and p16 (log2) showed correlation (r = 0.59; p < 0.05) in HPV-positive HNSCC tumor samples.
Figure 2
Figure 2
ELISA tests on HNSCC serum samples. Statistical significance was indicated as * for p < 0.05; (A) Serum antibody levels against HPV16 L1 in HNSCC patients. Differential OD between HPV-positive and HPV-negative patients (p < 0.05); (B) HPV16 L1 antibody variation during HPV-positive patient follow-up; (C) HPV16 E7 oncoprotein quantification in serum shows no difference between HPV-positive and HPV-negative patients (p > 0.05); (D) HPV16 E7 oncoprotein variation during HPV-positive patient follow-up.
Figure 3
Figure 3
Kaplan-Meier (KM) curves for RFS and OS in HNSCC; KM curves for (A) RFS and (B) OS for HPV DNA presence in HNSCC tumor samples; KM curves for (C) RFS and (D) OS for p16 over- or under-expression in HNSCC samples; KM curves for (E) RFS and (F) OS for HPV E7 mRNA expression in HNSCC tumor samples. Statistical significance was indicated as p < 0.01 or p < 0.05.
Figure 4
Figure 4
Kaplan-Meier (KM) curves for serological tests representing RFS and OS in HNSCC patients for HPV16 L1 and OPSCC for E7 oncoprotein; KM of (A) RFS and (B) OS for HPV16 L1 in HNSCC patients; KM of (C) RFS and (D) OS for HPV E7 oncoprotein in serum from HPV-positive OPSCC patients; KM of (E) RFS and (F) OS for increment or decrement of E7 oncoprotein in serum from OPSCC patients during follow-up. Statistical significance was indicated as p < 0.05.
Figure 5
Figure 5
Kaplan-Meier (KM) curves for tumor size (T), node status (N) and stage in HPV-positive HNSCC patients representing RFS and OS; KM representing (A) RFS and (B) OS for patients divided into tumor size: T (1–2) and T (3–4); KM representing (C) RFS and (D) OS for patients divided into node status: N0 and N+; KM representing (E) RFS and (F) OS for patients divided into stages I/II and III/IV; OS for patients divided into stages I/II and III/IV. Statistical significance was indicated as p < 0.05.
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