A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes
Abstract Background Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers ass...
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| Format: | Article |
| Language: | English |
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BMC
2017-09-01
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| Series: | BMC Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12916-017-0929-y |
| _version_ | 1819046922302783488 |
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| author | Jean-Philippe Foy Louis Bazire Sandra Ortiz-Cuaran Sophie Deneuve Janice Kielbassa Emilie Thomas Alain Viari Alain Puisieux Patrick Goudot Chloé Bertolus Nicolas Foray Youlia Kirova Pierre Verrelle Pierre Saintigny |
| author_facet | Jean-Philippe Foy Louis Bazire Sandra Ortiz-Cuaran Sophie Deneuve Janice Kielbassa Emilie Thomas Alain Viari Alain Puisieux Patrick Goudot Chloé Bertolus Nicolas Foray Youlia Kirova Pierre Verrelle Pierre Saintigny |
| author_sort | Jean-Philippe Foy |
| collection | DOAJ |
| description | Abstract Background Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease. Methods Gene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs). Results We identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the “atypical” molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor. Conclusions Our study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease. |
| first_indexed | 2024-12-21T10:52:10Z |
| format | Article |
| id | doaj.art-ec9aa0071c5c410486c5c03ee2b33199 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-12-21T10:52:10Z |
| publishDate | 2017-09-01 |
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| series | BMC Medicine |
| spelling | doaj.art-ec9aa0071c5c410486c5c03ee2b331992022-12-21T19:06:37ZengBMCBMC Medicine1741-70152017-09-0115111310.1186/s12916-017-0929-yA 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypesJean-Philippe Foy0Louis Bazire1Sandra Ortiz-Cuaran2Sophie Deneuve3Janice Kielbassa4Emilie Thomas5Alain Viari6Alain Puisieux7Patrick Goudot8Chloé Bertolus9Nicolas Foray10Youlia Kirova11Pierre Verrelle12Pierre Saintigny13Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de LyonDepartment of Radiation Oncology, Institut CurieUniv Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de LyonDepartment of Translational Research and Innovation, Centre Léon BérardPlatform of Bioninformatics-Gilles Thomas, Synergie Lyon CancerPlatform of Bioninformatics-Gilles Thomas, Synergie Lyon CancerPlatform of Bioninformatics-Gilles Thomas, Synergie Lyon CancerUniv Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de LyonDepartment of Oral and Maxillofacial Surgery, University of Pierre Marie Curie-Paris 6, Pitié-Salpêtrière HospitalDepartment of Oral and Maxillofacial Surgery, University of Pierre Marie Curie-Paris 6, Pitié-Salpêtrière HospitalUniv Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de LyonDepartment of Radiation Oncology, Institut CurieINSERM U 1196 , CNRS UMR 9187, Institut CurieUniv Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de LyonAbstract Background Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease. Methods Gene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs). Results We identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the “atypical” molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor. Conclusions Our study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease.http://link.springer.com/article/10.1186/s12916-017-0929-yHead neck squamous cell carcinomasMolecular subtypesPredictive biomarkerRadiation therapyRelapseResistance |
| spellingShingle | Jean-Philippe Foy Louis Bazire Sandra Ortiz-Cuaran Sophie Deneuve Janice Kielbassa Emilie Thomas Alain Viari Alain Puisieux Patrick Goudot Chloé Bertolus Nicolas Foray Youlia Kirova Pierre Verrelle Pierre Saintigny A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes BMC Medicine Head neck squamous cell carcinomas Molecular subtypes Predictive biomarker Radiation therapy Relapse Resistance |
| title | A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes |
| title_full | A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes |
| title_fullStr | A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes |
| title_full_unstemmed | A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes |
| title_short | A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes |
| title_sort | 13 gene expression based radioresistance score highlights the heterogeneity in the response to radiation therapy across hpv negative hnscc molecular subtypes |
| topic | Head neck squamous cell carcinomas Molecular subtypes Predictive biomarker Radiation therapy Relapse Resistance |
| url | http://link.springer.com/article/10.1186/s12916-017-0929-y |
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