Genetic and Epigenetic Changes of Components Affecting the WNT Pathway in Colorectal Carcinomas Stratified by Microsatellite Instability

Abstract

An unselected series of 310 colorectal carcinomas, stratified according to microsatellite instability (MSI) and DNA ploidy, was examined for mutations and/or promoter hypermethylation of five components of the WNT signaling cascade [APC, CTNNB1 (encoding beta-catenin), AXIN2, TCF4, and WISP3] and three genes indirectly affecting this pathway [CDH1 (encoding E-cadherin), PTEN, and TP53]. APC and TP53 mutations were each present more often in microsatellite-stable (MSS) tumors than in those with MSI (P < .001 for both). We confirmed that the aneuploid MSS tumors frequently contained TP53 mutations (P < .001), whereas tumors with APC mutations and/or promoter hypermethylation revealed no associations to ploidy. Mutations in APC upstream of codons 1020 to 1169, encoding the beta-catenin binding site, were found in 15/144 mutated tumors and these patients seemed to have poor clinical outcome (P = .096). Frameshift mutations in AXIN2, PTEN, TCF4, and WISP3 were found in 20%, 17%, 46%, and 28% of the MSI tumors, respectively. More than half of the tumors with heterozygote mutations in AXIN2 were concurrently mutated in APC. The present study showed that more than 90% of all samples had alteration in one or more of the genes investigated, adding further evidence to the vital importance of activated WNT signaling in colorectal carcinogenesis.

A gene marker panel covering the Wnt and the Ras-Raf-MEK-MAPK signalling pathways allows to detect gene mutations in 80% of early (UICC I) colon cancer stages in humans

“…In the case of APC similar results have been reported by Thorstensen et al [35], whereas in the case of K-RAS Konishi et al [36] and Jass et al [37] have shown that it is more frequently mutated in MSI-L than in MSS tumours. The CTNNB1 gene was only found to be mutated in 2 out of 50 tumours, which is in agreement with previously published data reporting that CTNNB1 mutations were present in up to 3% of the sporadic CRC analyzed [13][14][15][16] and that they are mainly associated with HNPCC [17].…”

A Serrated Colorectal Cancer Pathway Predominates over the Classic WNT Pathway in Patients with Hyperplastic Polyposis Syndrome

“…Although in these CRCs no APC-MCR mutations or CTNNB1 exon 4 to 10 hotspot mutations were identified, alternative mechanisms may be operational to activate the WNT pathway, eg, methylation of the APC promotor regions and MSIrelated frameshift mutations in WNT pathway regulators, such as AXIN2. 53 In these patients with HPS, a median of only one adenoma (range, zero to five) was identified, suggesting that the WNT pathway may, indeed, be involved at some stage of carcinogenesis via the serrated pathway. Considering that no BRAF mutations or directly adjacent serrated polyps were found, it seems unlikely that these CRCs are the outcome of a proposed fusion pathway, but formally this cannot be excluded.…”

Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines

“…This stop codon results in Axin2 transcripts without the DIX domain (761-843 aa), needed for b-catenin binding of Axin2. 30 However, the demonstration of a novel heterozygous in-frame deletion of AXIN2 exon 7 in a MSI2 cancer (2%, Conversion of glycine to an aspartic acid at codon 90 (G90D) in the second HEAT repeat of PPP2R1B has been reported previously in lung and colon cancer. 21 These authors suggested that this codon might represent a hot spot for mutation in cancers.…”