Schmitt, Katrin, Molfenter, Britta, Laureano, Natalia Koerich, Tawk, Bouchra, Bieg, Matthias, Hostench, Xavier Pastor, Weichenhan, Dieter, Ullrich, Nina D., Shang, Viny, Richter, Daniela, Stoegbauer, Fabian, Schroeder, Lea, de Bem Prunes, Bianca, Visioli, Fernanda, Rados, Pantelis Varvaki, Jou, Adriana, Plath, Michaela, Federspil, Philippe A., Thierauf, Julia, Doescher, Johannes, Weissinger, Stephanie E., Hoffmann, Thomas K., Wagner, Steffen, Wittekindt, Claus, Ishaque, Naveed ORCID: 0000-0002-8426-901X, Eils, Roland ORCID: 0000-0002-0034-4036, Klussmann, Jens P., Holzinger, Dana, Plass, Christoph, Abdollahi, Amir, Freier, Kolja, Weichert, Wilko, Zaoui, Karim and Hess, Jochen (2019). Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer. Int. J. Cancer, 145 (12). S. 3299 - 3311. HOBOKEN: WILEY. ISSN 1097-0215

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schmitt, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Molfenter, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laureano, Natalia KoerichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tawk, BouchraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bieg, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hostench, Xavier PastorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weichenhan, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Nina D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shang, VinyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richter, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoegbauer, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, LeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Bem Prunes, BiancaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Visioli, FernandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rados, Pantelis VarvakiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jou, AdrianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plath, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Federspil, Philippe A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thierauf, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doescher, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weissinger, Stephanie E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, Thomas K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittekindt, ClausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ishaque, NaveedUNSPECIFIEDorcid.org/0000-0002-8426-901XUNSPECIFIED
Eils, RolandUNSPECIFIEDorcid.org/0000-0002-0034-4036UNSPECIFIED
Klussmann, Jens P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzinger, DanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plass, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdollahi, AmirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freier, KoljaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weichert, WilkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zaoui, KarimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-124390
DOI: 10.1002/ijc.32481
Journal or Publication Title: Int. J. Cancer
Volume: 145
Number: 12
Page Range: S. 3299 - 3311
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1097-0215
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RECURRENT; IDENTIFICATION; EXPRESSION; LANDSCAPE; PROGNOSIS; LNCAP; HPVMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12439

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