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

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.

SUBMITTER: Krimpenfort P 

PROVIDER: S-EPMC6441055 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature