Receptor tyrosine kinase profiles and human papillomavirus status in oropharyngeal squamous cell carcinoma

Barbara Cortelazzi, Paolo Verderio, Chiara Maura Ciniselli, Sara Pizzamiglio, Paolo Bossi, Annunziata Gloghini, Ambra V. Gualeni, Chiara C. Volpi, Laura Locati, Marco A. Pierotti, Lisa Licitra, Silvana Pilotti, Federica Perrone

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OSCCs) are two distinct entities. We defined the molecular profiles of druggable receptor tyrosine kinases (RTKs) in both groups. Materials and methods: E5 expression and RTK alterations were studied in 17 HPV-positive and 59 HPV-negative formalin-fixed OSCCs. RTK activation was explored in further 12 frozen OSCCs. Results: The HPV-positive OSCCs showed E5 expression and 33.3% expressed low level of HER2. The HPV-negative OSCCs showed HER2 expression (31.2%), increased HER2 gene copy number (46.51%, P = 0.045) and HER2 activation through HER2/EGFR heterodimerisation; HER3 (51.06%, P = 0.008) and neuregulin (65.63%; P = 0.03) expression, HER3 activation and HER3/EGFR heterodimerisation; and increased IGF-1R copy number (40.50%, P = 0.021), high IGF-1R cDNA values (P = 0.002), IGF-1R activation and expression of IGF1/2 and amphiregulin. PI3KCA mutations/expression/increased gene copy number and PTEN mutations were found in both groups, whereas PTEN gene loss was only observed in the HPV-positive cases. Conclusion: Human papillomavirus-positive and HPV-negative OSCC showed different RTK profiles. In HPV-positive cases, it would be interesting to study the expression of E5, which may modulate EGFR turnover and activate VEGF and PDGFRβ. In HPV-negative cases, HER3 may be a promising druggable biomarker that deserves further investigation. PI3KCA and PTEN alterations encourage the promising clinical evaluation of PI3K/mTOR inhibitor activity in OSCC, particularly in HPV-positive/PI3KCA-mutated OSCCs because they may be driven by PI3KCA mutation alone.

Original languageEnglish
Pages (from-to)734-745
Number of pages12
JournalJournal of Oral Pathology and Medicine
Volume44
Issue number9
DOIs
Publication statusPublished - Oct 1 2015

Fingerprint

Receptor Protein-Tyrosine Kinases
Squamous Cell Carcinoma
Gene Dosage
Mutation
Neuregulins
erbB-2 Genes
Phosphatidylinositol 3-Kinases
Formaldehyde
Vascular Endothelial Growth Factor A
Complementary DNA
Biomarkers

Keywords

  • HER3
  • HR-HPV
  • IGF-1R
  • Oropharyngeal squamous cell carcinomas
  • PIK3CA

ASJC Scopus subject areas

  • Cancer Research
  • Pathology and Forensic Medicine
  • Otorhinolaryngology
  • Oral Surgery
  • Periodontics

Cite this

Receptor tyrosine kinase profiles and human papillomavirus status in oropharyngeal squamous cell carcinoma. / Cortelazzi, Barbara; Verderio, Paolo; Ciniselli, Chiara Maura; Pizzamiglio, Sara; Bossi, Paolo; Gloghini, Annunziata; Gualeni, Ambra V.; Volpi, Chiara C.; Locati, Laura; Pierotti, Marco A.; Licitra, Lisa; Pilotti, Silvana; Perrone, Federica.

In: Journal of Oral Pathology and Medicine, Vol. 44, No. 9, 01.10.2015, p. 734-745.

Research output: Contribution to journalArticle

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abstract = "Background: Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OSCCs) are two distinct entities. We defined the molecular profiles of druggable receptor tyrosine kinases (RTKs) in both groups. Materials and methods: E5 expression and RTK alterations were studied in 17 HPV-positive and 59 HPV-negative formalin-fixed OSCCs. RTK activation was explored in further 12 frozen OSCCs. Results: The HPV-positive OSCCs showed E5 expression and 33.3{\%} expressed low level of HER2. The HPV-negative OSCCs showed HER2 expression (31.2{\%}), increased HER2 gene copy number (46.51{\%}, P = 0.045) and HER2 activation through HER2/EGFR heterodimerisation; HER3 (51.06{\%}, P = 0.008) and neuregulin (65.63{\%}; P = 0.03) expression, HER3 activation and HER3/EGFR heterodimerisation; and increased IGF-1R copy number (40.50{\%}, P = 0.021), high IGF-1R cDNA values (P = 0.002), IGF-1R activation and expression of IGF1/2 and amphiregulin. PI3KCA mutations/expression/increased gene copy number and PTEN mutations were found in both groups, whereas PTEN gene loss was only observed in the HPV-positive cases. Conclusion: Human papillomavirus-positive and HPV-negative OSCC showed different RTK profiles. In HPV-positive cases, it would be interesting to study the expression of E5, which may modulate EGFR turnover and activate VEGF and PDGFRβ. In HPV-negative cases, HER3 may be a promising druggable biomarker that deserves further investigation. PI3KCA and PTEN alterations encourage the promising clinical evaluation of PI3K/mTOR inhibitor activity in OSCC, particularly in HPV-positive/PI3KCA-mutated OSCCs because they may be driven by PI3KCA mutation alone.",
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AU - Verderio, Paolo

AU - Ciniselli, Chiara Maura

AU - Pizzamiglio, Sara

AU - Bossi, Paolo

AU - Gloghini, Annunziata

AU - Gualeni, Ambra V.

AU - Volpi, Chiara C.

AU - Locati, Laura

AU - Pierotti, Marco A.

AU - Licitra, Lisa

AU - Pilotti, Silvana

AU - Perrone, Federica

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AB - Background: Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OSCCs) are two distinct entities. We defined the molecular profiles of druggable receptor tyrosine kinases (RTKs) in both groups. Materials and methods: E5 expression and RTK alterations were studied in 17 HPV-positive and 59 HPV-negative formalin-fixed OSCCs. RTK activation was explored in further 12 frozen OSCCs. Results: The HPV-positive OSCCs showed E5 expression and 33.3% expressed low level of HER2. The HPV-negative OSCCs showed HER2 expression (31.2%), increased HER2 gene copy number (46.51%, P = 0.045) and HER2 activation through HER2/EGFR heterodimerisation; HER3 (51.06%, P = 0.008) and neuregulin (65.63%; P = 0.03) expression, HER3 activation and HER3/EGFR heterodimerisation; and increased IGF-1R copy number (40.50%, P = 0.021), high IGF-1R cDNA values (P = 0.002), IGF-1R activation and expression of IGF1/2 and amphiregulin. PI3KCA mutations/expression/increased gene copy number and PTEN mutations were found in both groups, whereas PTEN gene loss was only observed in the HPV-positive cases. Conclusion: Human papillomavirus-positive and HPV-negative OSCC showed different RTK profiles. In HPV-positive cases, it would be interesting to study the expression of E5, which may modulate EGFR turnover and activate VEGF and PDGFRβ. In HPV-negative cases, HER3 may be a promising druggable biomarker that deserves further investigation. PI3KCA and PTEN alterations encourage the promising clinical evaluation of PI3K/mTOR inhibitor activity in OSCC, particularly in HPV-positive/PI3KCA-mutated OSCCs because they may be driven by PI3KCA mutation alone.

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