Genetic and Epigenetic Changes of Components Affecting the WNT Pathway in Colorectal Carcinomas Stratified by Microsatellite Instability1

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2005-02, Vol.7 (2), p.99-108
• Main Authors: Thorstensen, Lin, Lind, Guro E, Løvig, Tone, Diep, Chieu B, Meling, Gunn I, Rognum, Torleiv O, Lothe, Ragnhild A
• Format: Article
• Language: English
• ISSN: 1522-8002; 1476-5586

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 β-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 β-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.