Oncogenic KRAS is not necessary for Wnt signalling activation in APC-associated FAP adenomas

Abstract

Recent studies have suggested that APC loss alone may be insufficient to promote aberrant Wnt/Β-catenin signalling. Our aim was to comprehensively characterize Wnt signalling components in a set of APC-associated familial adenomatous polyposis (FAP) tumours. Sixty adenomas from six FAP patients with known pathogenic APC mutations were included. Somatic APC and KRAS mutations, Β-catenin immunostaining, and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analysed. Array-comparative genomic hybridization (aCGH) was also assessed in 26 FAP adenomas and 24 paired adenoma–carcinoma samples. A somatic APC alteration was present in 15 adenomas (LOH in 11 and four point mutations). KRAS mutations were detected in 10% of the cases. APC mRNA was overexpressed in adenomas. MYC and AXIN2 were also overexpressed, with significant intra-case heterogeneity. Increased cytoplasmic and/or nuclear Β-catenin staining was seen in 94% and 80% of the adenomas. Β-Catenin nuclear staining was strongly associated with MYC levels ( p value 0.03) but not with KRAS mutations. Copy number aberrations were rare. However, the recurrent chromosome changes observed more frequently contained Wnt pathway genes ( p value 0.012). Based on Β-catenin staining and Wnt pathway target genes alterations the Wnt pathway appears to be constitutively activated in all APC-FAP tumours, with alterations occurring both upstream and downstream of APC. Wnt aberrations are present at both the DNA and the RNA level. Somatic profiling of APC-FAP tumours provides new insights into the role of APC in tumourigenesis. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.