Cancers (Jul 2022)
Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients
- 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
Affiliations
- Julia Hess
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Kristian Unger
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Cornelius Maihoefer
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Lars Schüttrumpf
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Peter Weber
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Sebastian Marschner
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Ludmila Wintergerst
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Ulrike Pflugradt
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Philipp Baumeister
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Axel Walch
- Research Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Christine Woischke
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
- Thomas Kirchner
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
- Martin Werner
- Institute for Surgical Pathology, Medical Center-University of Freiburg, 79106 Freiburg, Germany
- Kristin Sörensen
- Institute for Surgical Pathology, Medical Center-University of Freiburg, 79106 Freiburg, Germany
- Michael Baumann
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Ingeborg Tinhofer
- Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, 10117 Berlin, Germany
- Stephanie E. Combs
- German Cancer Consortium (DKTK), Partner Site Munich, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Jürgen Debus
- Department of Radiation Oncology, Heidelberg Ion Therapy Center (HIT), University of Heidelberg, 69120 Heidelberg, Germany
- Henning Schäfer
- German Cancer Consortium (DKTK), Partner Site Freiburg, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Mechthild Krause
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Annett Linge
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Jens von der Grün
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, 60596 Frankfurt, Germany
- Martin Stuschke
- Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
- Daniel Zips
- Department of Radiation Oncology, Faculty of Medicine and University Hospital Tübingen, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
- Martin Canis
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Kirsten Lauber
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Ute Ganswindt
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Michael Henke
- German Cancer Consortium (DKTK), Partner Site Freiburg, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Horst Zitzelsberger
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- Claus Belka
- Clinical Cooperation Group “Personalized Radiotherapy in Head and Neck Cancer”, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- DOI
- https://doi.org/10.3390/cancers14153745
- Journal volume & issue
-
Vol. 14,
no. 15
p. 3745
Abstract
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.
Keywords