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Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer |
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| Authors: | Katrin Schmitt Britta Molfenter Natalia Koerich Laureano Bouchra Tawk Matthias Bieg Xavier Pastor Hostench Dieter Weichenhan Nina D. Ullrich Viny Shang Daniela Richter Fabian Stögbauer Lea Schroeder Bianca de Bem Prunes Fernanda Visioli Pantelis Varvaki Rados Adriana Jou Michaela Plath Philippe A. Federspil Julia Thierauf Johannes Döscher Stephanie E. Weissinger Thomas K. Hoffmann Steffen Wagner Claus Wittekindt Naveed Ishaque Roland Eils Jens P. Klussmann Dana Holzinger Christoph Plass Amir Abdollahi Kolja Freier Wilko Weichert Karim Zaoui Jochen Hess |
| Affiliation: | 1. Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany;2. Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany Oral Pathology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;3. Division of Molecular and Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg University Hospital, and Translational Radiation Oncology, German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany;4. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), and Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Heidelberg, Germany;5. Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany;6. Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Heidelberg, Germany;7. Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany;8. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany;9. Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Heidelberg, Germany;10. Oral Pathology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;11. Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany;12. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Ulm, Ulm, Germany;13. Institute of Pathology, University Hospital Ulm, Ulm, Germany;14. Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany;15. Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany;16. Department of Oral and Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany;17. Institute of Pathology, Technical University Munich (TUM), and German Cancer Consortium (DKTK) partner site, Munich, Germany |
| Abstract: | Genomic sequencing projects unraveled the mutational landscape of head and neck squamous cell carcinoma (HNSCC) and provided a comprehensive catalog of somatic mutations. However, the limited number of significant cancer-related genes obtained so far only partially explains the biological complexity of HNSCC and hampers the development of novel diagnostic biomarkers and therapeutic targets. We pursued a multiscale omics approach based on whole-exome sequencing, global DNA methylation and gene expression profiling data derived from tumor samples of the HIPO-HNC cohort (n = 87), and confirmed new findings with datasets from The Cancer Genome Atlas (TCGA). Promoter methylation was confirmed by MassARRAY analysis and protein expression was assessed by immunohistochemistry and immunofluorescence staining. We discovered a set of cancer-related genes with frequent somatic mutations and high frequency of promoter methylation. This included the ryanodine receptor 2 (RYR2), which showed variable promoter methylation and expression in both tumor samples and cell lines. Immunohistochemical staining of tissue sections unraveled a gradual loss of RYR2 expression from normal mucosa via dysplastic lesion to invasive cancer and indicated that reduced RYR2 expression in adjacent tissue and precancerous lesions might serve as risk factor for unfavorable prognosis and upcoming malignant conversion. In summary, our data indicate that impaired RYR2 function by either somatic mutation or epigenetic silencing is a common event in HNSCC pathogenesis. Detection of RYR2 expression and/or promoter methylation might enable risk assessment for malignant conversion of dysplastic lesions. |
| Keywords: | DNA methylation HNSCC RYR2 head and neck cancer omics analysis |