The integrative genomic and transcriptomic data revealed potential driver genes mapped in 11q13 associated with worse prognosis and response to treatment, giving fundamentals for the identification of novel therapeutic targets in OPSCC.

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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

The treatment currently considered standard for advanced oropharyngeal tumors involves concomitant chemo- and radiotherapy or surgery followed by adjuvant chemo- and radiotherapy. However, only 30 to 50% of patients with locally advanced disease survive more than three years, even with the advances in surgical techniques and the recognized benefits of therapy combined with radio- and chemotherapy. Treatment with induction TPF (docetaxel plus cisplatin and fluorouracil) chemotherapy followed by chemoradiotherapy was associated with a trend toward improved survival (Posner et al., 2007. N Engl J Med. 357:1705). The aim of this study was to investigate biological markers as potential predictors of response to chemotherapy and/or radiotherapy according to HPV infection in oropharyngeal carcinomas (OC). Thirty-two OC were evaluated by array CGH (4x180k, Agilent). A total of 35% of cases were HPV positives; HPV16 subtype was the most frequently detected (8/37), followed by subtype 18 (2/37). In general, HPV- cases showed a large number of copy number alterations (117 CNAs) in comparison with HPV+ samples. Losses on 7q22.1 and 14q12 were found exclusively in HPV+ tumors (p=0.044). Comparative analysis of genomic alterations among the patients which received combined chemoradiotherapy (22 cases) was done aiming to identify molecular markers that could predict the complete response (CR), partial response (PR) to treatment or progressive disease (PD). Tumors with CR showed a lower number of genomic alterations (90 CNAs versus 110 per cases in PR and PD). Losses at 1p21.3-p21.1 and gains on 10p13-p12.33 and 10p12.31-p12.1(p≤0.017) were exclusively found in patients with PD and PR. Overall survival (OS) analysis between HPV- and HPV+ cases demonstrated no significant differences (p>0.05). HPV- tumors showed more complexity and genomic instability than HPV+ tumors. Genomic losses or gains at different loci have been reported in HPV- compared to few or no alterations in HPV+ cases. In this study, it was detected specific chromosomal imbalances associated with therapy response and consequently, putative candidates to be validated in a large series of cases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1145. doi:1538-7445.AM2012-1145