A common human skin tumour is caused by activating mutations in beta-catenin

WNT signalling orchestrates a number of developmental programs(1-3), In res ponse to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is sta bilized, enabling downstream transcriptional activation by members of the L EF/TCF family(4,5). One of the target genes for beta-catenin/TCF encodes c- MYC, explaining why constitutive activation of the WNT pathway can lead to cancer, particularly in the colon(6). Most colon cancers arise from mutatio ns in the gene encoding adenomatous polyposis coli (APC), a protein require d for ubiquitin-mediated degradation of beta-catenin(7), but a small percen tage of colon and some other cancers harbour beta-catenin-stabilizing mutat ions (refs 8-17). Recently, we discovered that transgenic mice expressing a n activated beta-catenin are predisposed to developing skin tumours resembl ing pilomatricoma(18). Given that the skin of these adult mice also exhibit s signs of de novo hair-follicle morphogenesis, we wondered whether human p ilomatricomas might originate from hair matrix cells and whether they might possess beta-catenin-stabilizing mutations. Here, we explore the cell orig in and aetiology of this common human skin tumour. We found nuclear LEF-1 i n the dividing tumour cells, providing biochemical evidence that pilomatric omas are derived from hair matrix cells. At least 75% of these tumours poss ess mutations affecting the amino-terminal segment, normally involved in ph osphorylation-dependent, ubiquitin-mediated degradation of the protein. Thi s percentage of CTNNB1 mutations is greater than in all other human tumours examined thus far, and directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans.