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

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Cdkn2ab knockout mice develop skin carcinomas.
• The incidence of these carcinomas decreases with backcrossing to the FVB/N background.

Purpose of the Study:

• To investigate the genetic basis of the decreasing cancer phenotype in Cdkn2ab knockout mice.
• To identify the specific gene and its mechanism responsible for skin carcinoma development.

Main Methods:

• Microsatellite analysis to link the cancer phenotype to a chromosomal region.
• Wnt7b gene expression analysis in tumors and cell lines.
• ChIP-seq to identify active enhancers near Wnt7b.
• In vitro transformation assays of Cdkn2ab-deficient cell lines.

Main Results:

• The cancer phenotype is linked to a 20 Mb region on chromosome 15 of the 129P2 background, containing the Wnt7b gene.
• The 129P2 allele of Wnt7b is preferentially expressed in skin carcinomas and cell lines.
• H3K27-Ac enrichment in the 5' region of the Wnt7b 129P2 gene indicates active enhancer function.
• The Wnt7b 129P2 allele transforms Cdkn2ab-deficient cells in vitro, primarily via CDK6 activation.

Conclusions:

• The Cdkn2ab locus is critical for suppressing the oncogenic potential of WNT signaling.
• The Wnt7b 129P2 allele contributes to skin carcinoma development in Cdkn2ab knockout mice.
• Integrating somatically acquired lesions can improve genome-wide association studies for cancer predisposition.