C Dubot1, V Bernard2, M P Sablin3, S Vacher4, W Chemlali4, A Schnitzler4, G Pierron5, K Ait Rais5, N Bessoltane2, E Jeannot6, J Klijanienko6, O Mariani6, T Jouffroy7, V Calugaru8, C Hoffmann7, M Lesnik7, N Badois7, F Berger9, C Le Tourneau10, M Kamal3, I Bieche11. 1. Department of Medical Oncology, Institut Curie, Paris, Saint-Cloud, France; Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France. Electronic address: coraline.dubot@curie.fr. 2. Unit of Bioinformatics, Next Generation Sequencing Platform-ICGex, Institut Curie, Paris, France. 3. Department of Medical Oncology, Institut Curie, Paris, Saint-Cloud, France. 4. Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France. 5. Unit of Somatic Genomics, Department of Genetics, Institut Curie, Paris, France. 6. Department of Biopathology, Institut Curie, Paris, France. 7. Department of Surgery, Institut Curie, Paris, France. 8. Department of Radiotherapy, Institut Curie, Paris, France. 9. Department of Biostatistics, Institut Curie, Paris, France. 10. Department of Medical Oncology, Institut Curie, Paris, Saint-Cloud, France; INSERM U900 Research Unit, Saint-Cloud, France. 11. Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France; EA7331, Paris Descartes University, Faculty of Pharmaceutical and Biological Sciences, Paris, France.
Abstract
BACKGROUND: We aimed at identifying deleterious genomic alterations from untreated head and neck squamous cell carcinoma (HNSCC) patients, and assessing their prognostic value. PATIENTS AND METHODS: We retrieved 122 HNSCC patients who underwent primary surgery. Targeted NGS was used to analyse a panel of 100 genes selected among the most frequently altered genes in HNSCC and potential therapeutic targets. We selected only deleterious (activating or inactivating) single nucleotide variations, and copy number variations for analysis. Univariate and multivariate analyses were performed to assess the prognostic value of altered genes. RESULTS: A median of 2 (range: 0-10) genomic alterations per sample was observed. Most frequently altered genes involved the cell cycle pathway (TP53 [60%], CCND1 [30%], CDKN2A [25%]), the PI3K/AKT/MTOR pathway (PIK3CA [12%]), tyrosine kinase receptors (EGFR [9%], FGFR1 [5%]) and cell differentiation (FAT1 [7%], NOTCH1 [4%]). TP53 mutations (p = 0.003), CCND1 amplifications (p = 0.04), CDKN2A alterations (p = 0.02) and FGFR1 amplifications (p = 0.003), correlated with shorter overall survival (OS). The number of genomic alterations was significantly higher in the HPV-negative population (p = 0.029) and correlated with a shorter OS (p < 0.0001). Only TP53 mutation and FGFR1 amplification status remained statistically significant in the multivariate analysis. CONCLUSION: These results suggest that genomic alterations involving the cell cycle (TP53, CCND1, CDKN2A), as well as FGFR1 amplifications and tumour genomic alterations burden are prognostic biomarkers and might be therapeutic targets for patients with HNSCC.
BACKGROUND: We aimed at identifying deleterious genomic alterations from untreated head and neck squamous cell carcinoma (HNSCC) patients, and assessing their prognostic value. PATIENTS AND METHODS: We retrieved 122 HNSCCpatients who underwent primary surgery. Targeted NGS was used to analyse a panel of 100 genes selected among the most frequently altered genes in HNSCC and potential therapeutic targets. We selected only deleterious (activating or inactivating) single nucleotide variations, and copy number variations for analysis. Univariate and multivariate analyses were performed to assess the prognostic value of altered genes. RESULTS: A median of 2 (range: 0-10) genomic alterations per sample was observed. Most frequently altered genes involved the cell cycle pathway (TP53 [60%], CCND1 [30%], CDKN2A [25%]), the PI3K/AKT/MTOR pathway (PIK3CA [12%]), tyrosine kinase receptors (EGFR [9%], FGFR1 [5%]) and cell differentiation (FAT1 [7%], NOTCH1 [4%]). TP53 mutations (p = 0.003), CCND1 amplifications (p = 0.04), CDKN2A alterations (p = 0.02) and FGFR1 amplifications (p = 0.003), correlated with shorter overall survival (OS). The number of genomic alterations was significantly higher in the HPV-negative population (p = 0.029) and correlated with a shorter OS (p < 0.0001). Only TP53 mutation and FGFR1 amplification status remained statistically significant in the multivariate analysis. CONCLUSION: These results suggest that genomic alterations involving the cell cycle (TP53, CCND1, CDKN2A), as well as FGFR1 amplifications and tumour genomic alterations burden are prognostic biomarkers and might be therapeutic targets for patients with HNSCC.
Authors: Mohamed E Salem; Alberto Puccini; Joanne Xiu; Derek Raghavan; Heinz-Josef Lenz; W Michael Korn; Anthony F Shields; Philip A Philip; John L Marshall; Richard M Goldberg Journal: Oncologist Date: 2018-06-04
Authors: Paul B M Essers; Martijn van der Heijden; David Vossen; Reinout H de Roest; C René Leemans; Ruud H Brakenhoff; Michiel W M van den Brekel; Harry Bartelink; Marcel Verheij; Conchita Vens Journal: Int J Cancer Date: 2020-03-30 Impact factor: 7.396