Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients
| Autor: | Julia Hess, Kristian Unger, Cornelius Maihoefer, Lars Schüttrumpf, Peter Weber, Sebastian Marschner, Ludmila Wintergerst, Ulrike Pflugradt, Philipp Baumeister, Axel Walch, Christine Woischke, Thomas Kirchner, Martin Werner, Kristin Sörensen, Michael Baumann, Ingeborg Tinhofer, Stephanie E. Combs, Jürgen Debus, Henning Schäfer, Mechthild Krause, Annett Linge, Jens von der Grün, Martin Stuschke, Daniel Zips, Martin Canis, Kirsten Lauber, Ute Ganswindt, Michael Henke, Horst Zitzelsberger, Claus Belka |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Cancers; Volume 14; Issue 15; Pages: 3745 Cancers 14:3745 (2022) |
| Popis: | CA extern Simple Summary Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC), regarded as a distinct clinical entity, are characterized by a considerably favourable prognosis after radio(chemo)therapy and a not yet fully understood distinct molecular pathogenesis. We aimed to develop a miRNA-signature that identifies HPV-associated HNSCC according to their specific molecular pathogenesis, and to characterise the transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of n = 229 HPV characterized HNSCC specimens of patients treated by adjuvant radio(chemo) therapy. Using lasso-regression, a 24-miRNA signature predicting HPV-status was built in a multicentre cohort and validated in a single-centre cohort. Its combination with p16/HPV DNA status improved clinically relevant risk stratification, allowed the identification of an HPV-associated patient subgroup with impaired overall survival, and might be considered for future clinical decision-making. miRNA-transcriptome integration identified HPV-specific signaling pathways. Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours (n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK, Estrogen, EGFR, TGFbeta, WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD-L1 expression/PD-1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC. |
| Databáze: | OpenAIRE |
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