Abstract 1916: Integrative analysis of DNA copy number and gene expression in oropharyngeal squamous cell carcinomas .

Abstract

Abstract Head and neck squamous cell carcinomas (HNSCC) are the sixth prevalent cancer by incidence worldwide. The major risk factors associated with HNSCC are tobacco usage, alcohol consumption and human papillomavirus (HPV) infection. Only 40%-50% of patients survive more than three years, even with the advances in surgical techniques and the recognized benefits of chemotherapy. Integrative studies using genomic alterations and large-scale expression analysis have been used to find functionally relevant molecular drivers and targets for therapy. The aim of this study was to investigate biological markers as potential predictors of response to chemo and radiotherapy according to HPV infection in oropharyngeal carcinomas (OC). Thirty-three fresh OC biopsies were genotyped for HPV, evaluated by array CGH (4x180k, Agilent) and by gene expression large-scale analysis (4x44k, Agilent). Approximately 54% of cases were HPV positive with HPV16 (16/33) being the most frequently detected, followed by HPV 18 (1/33) and HPV 16/18 (1/33). The most frequent copy number alterations were losses on 8p11.23-p11.22, 14q11.1-q11.2, 15q11.2 and gains on 11q13.2 and 11q13.2-q13.3 (p<0.05). Comparative analysis of genomic alterations according to HPV status revealed gains of 3q26.31 and 11q13.2 and losses of 9p21.3 exclusively in HPV negative cases (p<0.05). Gains of 11q13.2-q13.4 were statistically associated with progressive disease. The amplicon 11q13 (where is mapped CCND1, FADD and PPFIA1) is frequently reported as involved in HNSCC. In this study this amplicon was associated with progressive disease and unfavorable prognosis. In agreement with literature, the majority of unfavorable treatment response cases were HPV negative (71.4%). These cases presented more CNAs compared to HPV positive cases. According to HPV status, it was identified 798 differentially expressed genes, 407 down- and 391 up-regulated. The integrative analysis using genomic and transcriptomic data was performed using R tools (positive correlation: R>0.5 and negative: R<0.5). It was identified 61 genes correlated by both procedures, 52 showed positive correlation (10/52 gain/up-regulated and 42/52 deletion/down-regulated) and 9 negative correlation (4/9 gain/down-regulated and 5/9 loss/up-regulated). Both genes mapped on 11q13, CCND1 and PPFIA1, were confirmed as associated with unfavorable response to treatment in OC, showing copy number gains and transcripts overexpression. This analysis demonstrated biological markers as potential predictors of response to chemotherapy and/or radiotherapy according to HPV infection in oropharyngeal carcinomas. Citation Format: Marcia Hatakeyama, Luciana A. Reis-Rosa, Fabio A. Marchi, Graziela Spilborghs, André L. Carvalho, Ulisses M. Ribaldo, Luiz P. Kowalski, Silvia R. Rogatto. Integrative analysis of DNA copy number and gene expression in oropharyngeal squamous cell carcinomas . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1916. doi:10.1158/1538-7445.AM2013-1916