title: Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma.
abstract: Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: hidetaka@surgpath.med.kyushu-u.ac.jp.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Torahiko
authors.initials: T
authors.lastname: Nakashima
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Nishijima
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satoh
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Hatanaka
authors.affiliation: Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shiratsuchi
authors.affiliation: Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Yasumatsu
authors.affiliation: Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Toh
authors.affiliation: Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Komune
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology*; D059248:Chemoradiotherapy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D056915:DNA Copy Number Variations; D004279:DNA, Viral / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology*; D061809:Human Papillomavirus DNA Tests; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009959:Oropharyngeal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology*; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000401:mortality / Q000821:virology*; D015995:Prevalence; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; C117307:KRAS protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EGFR; Human papillomavirus; In situ hybridization; Oropharyngeal squamous cell carcinoma; RAS; p16