A natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis

Paul Krimpenfort, Margriet Snoek, Jan-Paul Lambooij, Ji-Ying Song, Robin Weide, Rajith Bhaskaran, Hans Teunissen, David J. Adams, Elzo Wit and Anton Berns ()
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Paul Krimpenfort: The Netherlands Cancer Institute, Plesmanlaan 121
Margriet Snoek: The Netherlands Cancer Institute, Plesmanlaan 121
Jan-Paul Lambooij: The Netherlands Cancer Institute, Plesmanlaan 121
Ji-Ying Song: The Netherlands Cancer Institute, Plesmanlaan 121
Robin Weide: The Netherlands Cancer Institute, Plesmanlaan 121
Rajith Bhaskaran: The Netherlands Cancer Institute, Plesmanlaan 121
Hans Teunissen: The Netherlands Cancer Institute, Plesmanlaan 121
David J. Adams: Wellcome Genome Campus
Elzo Wit: The Netherlands Cancer Institute, Plesmanlaan 121
Anton Berns: The Netherlands Cancer Institute, Plesmanlaan 121

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09321-8

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