A natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis
| Autor: | Robin H. van der Weide, Ji-Ying Song, David J. Adams, Elzo de Wit, Rajith Bhaskaran, Hans Teunissen, Margriet Snoek, Jan-Paul Lambooij, Paul Krimpenfort, Anton Berns |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Skin Neoplasms Carcinogenesis Genetic Linkage Science General Physics and Astronomy Locus (genetics) 02 engineering and technology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Cell Line Tumor medicine Animals Allele Enhancer lcsh:Science Base Pairing Lung Wnt Signaling Pathway Alleles Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinase Inhibitor p15 Mice Knockout Platelet-Derived Growth Factor Metaplasia Multidisciplinary biology Wnt signaling pathway Genetic Variation General Chemistry Cyclin-Dependent Kinase 6 Fibroblasts 021001 nanoscience & nanotechnology Phenotype Chromosomes Mammalian 3. Good health 030104 developmental biology Cell Transformation Neoplastic Knockout mouse biology.protein Cancer research lcsh:Q Cyclin-dependent kinase 6 0210 nano-technology |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-10 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Cdkn2ab knockout mice, generated from 129P2 ES cells develop skin carcinomas. Here we show that the incidence of these carcinomas drops gradually in the course of backcrossing to the FVB/N background. Microsatellite analyses indicate that this cancer phenotype is linked to a 20 Mb region of 129P2 chromosome 15 harboring the Wnt7b gene, which is preferentially expressed from the 129P2 allele in skin carcinomas and derived cell lines. ChIPseq analysis shows enrichment of H3K27-Ac, a mark for active enhancers, in the 5’ region of the Wnt7b 129P2 gene. The Wnt7b 129P2 allele appears sufficient to cause in vitro transformation of Cdkn2ab-deficient cell lines primarily through CDK6 activation. These results point to a critical role of the Cdkn2ab locus in keeping the oncogenic potential of physiological levels of WNT signaling in check and illustrate that GWAS-based searches for cancer predisposing allelic variants can be enhanced by including defined somatically acquired lesions as an additional input. Cdkn2ab knockout mice develop skin tumours but this phenotype is lost on backcrossing of the mice. Here, the authors describe a genetic variant encompassing Wnt7b that synergises with Cdkn2ab loss and is required for tumour formation in these mice. |
| Databáze: | OpenAIRE |
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