Haitham Mirghani1, Nicolas Ugolin2, Catherine Ory2, Marine Lefèvre3, Sylvain Baulande4, Paul Hofman5, Jean Lacau St Guily6, Sylvie Chevillard2, Roger Lacave7. 1. ER2 unit and GRC10, Université Pierre et Marie Curie, Paris, France; Department of Head and Neck Surgery, Institut de Cancérologie Gustave Roussy, Villejuif, France. Electronic address: haitham.mirghani@gustaveroussy.fr. 2. CEA, DSV, iRCM, Laboratory of Experimental Cancerology, BP64, 92265 Fontenay-aux-Roses Cedex, France. 3. Department of Pathology, GHUEP, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, France. 4. PartnerChip, Bat. G2, Genopole Campus 2, Evry, France. 5. Laboratory of Clinical and Experimental Pathology and Biobank of CHUN, Pasteur Hospital, Nice F-06001, France. 6. ER2 unit and GRC10, Université Pierre et Marie Curie, Paris, France; Department of Otolaryngology-Head and Neck Surgery, GHUEP, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, France. 7. ER2 unit and GRC10, Université Pierre et Marie Curie, Paris, France; Tumours Genomic Unit, GHUEP, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, France.
Abstract
OBJECTIVE: Human-papillomaviruses (HPV) type 16 is a causative agent in an increasing subset of oropharyngeal squamous cell carcinomas (OPSCCs). These tumors have distinct oncogenic mechanisms and a more favorable prognosis than tobacco-induced OPSCCs. Although these differences emphasize the need for a specific therapeutic approach, HPV status is still not used to guide treatment. A better characterization of the molecular profile related to HPV16-induced OPSCC might help to develop personalized treatments. PATIENTS AND METHODS: Using a human whole-genome DNA-microarray, we have examined the gene expression profiles in 15 HPV-negative and 15 transcriptionally-active HPV-positive OPSCCs. The study was conducted in two steps. Firstly, a learning/training-set consisting of 8 HPV16-positive and 8 HPV16-negative OPSCCs was analyzed to identify a specific signature. Potentially confounding factors (stage, sex and tobacco) were equally distributed in both groups. Subsequently the robustness of this signature was confirmed by blind case-by-case classification of a validation-set composed of the 14 remaining tumors. RESULTS: We have identified a signature composed of 224 genes, which discriminates HPV16-induced OPSCC from their HPV-negative counterparts. After the blind classification of the 14 tumours, the viral status was revealed: 13 out of 14 tumors were correctly classified according to tumor etiology, 1/14 was not determined and none were misclassified. Several of the differentially expressed genes were involved in cell-cycle regulation, DNA replication and repair, transcription regulation, immune response and apoptosis. CONCLUSION: Our study contributes to a better understanding of pathogenic mechanisms involved in the development of HPV-positive OPSCCs and in the identification of potential therapeutic targets.
OBJECTIVE:Human-papillomaviruses (HPV) type 16 is a causative agent in an increasing subset of oropharyngeal squamous cell carcinomas (OPSCCs). These tumors have distinct oncogenic mechanisms and a more favorable prognosis than tobacco-induced OPSCCs. Although these differences emphasize the need for a specific therapeutic approach, HPV status is still not used to guide treatment. A better characterization of the molecular profile related to HPV16-induced OPSCC might help to develop personalized treatments. PATIENTS AND METHODS: Using a human whole-genome DNA-microarray, we have examined the gene expression profiles in 15 HPV-negative and 15 transcriptionally-active HPV-positive OPSCCs. The study was conducted in two steps. Firstly, a learning/training-set consisting of 8 HPV16-positive and 8 HPV16-negative OPSCCs was analyzed to identify a specific signature. Potentially confounding factors (stage, sex and tobacco) were equally distributed in both groups. Subsequently the robustness of this signature was confirmed by blind case-by-case classification of a validation-set composed of the 14 remaining tumors. RESULTS: We have identified a signature composed of 224 genes, which discriminates HPV16-induced OPSCC from their HPV-negative counterparts. After the blind classification of the 14 tumours, the viral status was revealed: 13 out of 14 tumors were correctly classified according to tumor etiology, 1/14 was not determined and none were misclassified. Several of the differentially expressed genes were involved in cell-cycle regulation, DNA replication and repair, transcription regulation, immune response and apoptosis. CONCLUSION: Our study contributes to a better understanding of pathogenic mechanisms involved in the development of HPV-positive OPSCCs and in the identification of potential therapeutic targets.
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