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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
Author(s) -
Schmitt Katrin,
Molfenter Britta,
Laureano Natalia Koerich,
Tawk Bouchra,
Bieg Matthias,
Hostench Xavier Pastor,
Weichenhan Dieter,
Ullrich Nina D.,
Shang Viny,
Richter Daniela,
Stögbauer Fabian,
Schroeder Lea,
Bem Prunes Bianca,
Visioli Fernanda,
Rados Pantelis Varvaki,
Jou Adriana,
Plath Michaela,
Federspil Philippe A.,
Thierauf Julia,
Döscher Johannes,
Weissinger Stephanie E.,
Hoffmann Thomas K.,
Wagner Steffen,
Wittekindt Claus,
Ishaque Naveed,
Eils Roland,
Klussmann Jens P.,
Holzinger Dana,
Plass Christoph,
Abdollahi Amir,
Freier Kolja,
Weichert Wilko,
Zaoui Karim,
Hess Jochen
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32481
Subject(s) - biology , dna methylation , methylation , cancer research , head and neck squamous cell carcinoma , cancer , somatic cell , epigenetics , pathology , head and neck cancer , gene expression , gene , genetics , medicine
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.