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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

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...

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Main Authors: Schmitt, Katrin (Author) , Laureano, Natalia K. (Author) , Bieg, Matthias (Author) , Weichenhan, Dieter (Author) , Ullrich, Nina D. (Author) , Stögbauer, Fabian (Author) , Jou, Adriana (Author) , Plath, Michaela (Author) , Federspil, Philippe A. (Author) , Thierauf, Julia (Author) , Abdollahi, Amir (Author) , Freier, Kolja (Author) , Plath, Karim (Author) , Heß, Jochen (Author)
Format: Article (Journal)
Language:English
Published: [15 December 2019]
In: International journal of cancer
Year: 2019, Volume: 145, Issue: 12, Pages: 3299-3310
ISSN:1097-0215
DOI:10.1002/ijc.32481
Online Access:Verlag, Volltext: https://doi.org/10.1002/ijc.32481
Verlag, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32481
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Author Notes: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 and Jochen Hess
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Summary: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.
Item Description:First published: 28 May 2019
Gesehen am 04.11.2019
Physical Description:Online Resource
ISSN:1097-0215
DOI:10.1002/ijc.32481

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