Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer
| Autor: | Pantelis Varvaki Rados, Kolja Freier, Daniela Richter, Amir Abdollahi, Matthias Bieg, Jochen Hess, Karim Zaoui, Adriana Jou, Stephanie E. Weissinger, Viny Shang, Nina D. Ullrich, Steffen Wagner, Christoph Plass, Jens Peter Klussmann, Thomas K. Hoffmann, Julia Thierauf, Roland Eils, Fabian Stögbauer, Britta Molfenter, Bianca De Bem Prunes, Wilko Weichert, Lea Schroeder, Michaela Plath, Naveed Ishaque, P.A. Federspil, Bouchra Tawk, Dana Holzinger, Fernanda Visioli, Claus Wittekindt, Natalia Koerich Laureano, Dieter Weichenhan, J Döscher, Xavier Pastor Hostench, Katrin Schmitt |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Cancer Research Somatic cell Biology Epigenesis Genetic Cohort Studies 03 medical and health sciences 0302 clinical medicine Germline mutation Cell Line Tumor medicine Humans ddc:610 Promoter Regions Genetic Gene Aged Aged 80 and over Squamous Cell Carcinoma of Head and Neck Gene Expression Profiling Promoter Ryanodine Receptor Calcium Release Channel Methylation DNA Methylation Middle Aged medicine.disease Prognosis Head and neck squamous-cell carcinoma Gene expression profiling Gene Expression Regulation Neoplastic Oncology Head and Neck Neoplasms 030220 oncology & carcinogenesis DNA methylation Mutation Cancer research CpG Islands Female |
| Zdroj: | International journal of cancerReferences. 145(12) |
| ISSN: | 1097-0215 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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