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Molecular and Cytogenetic Subgroups of Oropharyngeal Squamous Cell Carcinoma

Authors' Affiliations: ¹ Unit of Experimental Molecular Pathology, ² Department of Pathology; ³ Head and Neck Cancer Medical Oncology Unit, and Departments of ⁴ Head and Neck Surgery and ⁵ Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori; and ⁶ Istituto Fondazione Italiana Ricerca Cancro di Oncologia Molecolare, Fondazione Italiana Ricerca Cancro, Institute of Molecular Oncology, Milan, Italy

Requests for reprints: Silvana Pilotti, Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-2-2390-2293; Fax: 39-2-2390-2198; E-mail: silvana.pilotti{at}istitutotumori.mi.it.

Purpose: The aim of this study was to acquire further insights into the pathogenetic pathways of head and neck squamous cell carcinomas (HNSCC) that may be useful for identifying new biomarkers instrumental in developing more specific treatment approaches.

Experimental Design: Cell cycle regulators and epidermal growth factor receptor (EGFR) and BRAF genes were analyzed in a series of 90 oropharyngeal SCCs of a cohort of surgically treated patients from a single institution, and the results were matched with the presence of high-risk human papillomavirus (HR-HPV) DNA and the TP53 status.

Results: At least four distinct groups of tumors were identified sharing a common histology but displaying different molecular/cytogenetic patterns: (a) 19% were HPV-positive SCCs whose lack of alterations of the investigated genes could explain their particular natural history, which requires less aggressive treatment; (b) 37% were HPV-negative SCCs carrying TP53 mutations, which may be more effectively treated by drugs acting through p53-independent apoptosis; (c) 34% were HPV-negative SCCs carrying wild-type TP53 and loss of 9p21 (p16^INK4a and p15^INK4b) and/or cyclin D1 overexpression that justify treatment with DNA-damaging drugs followed by cell cycle inhibitors; and (d) 10% were HPV-negative lacking tumor suppressor genes and cell cycle alterations. The second, third, and fourth groups also showed an increased copy number of EGFR and chromosome 7 (43%) that might justify the additional or alternative use of EGFR inhibitors.

Conclusions: Our findings suggest that assessing HPV, TP53, 9p21, and EGFR status may be crucial to finding more tailored and beneficial treatments for oropharyngeal SCCs.

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