Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability

被引:113
作者
Thorstensen, L
Lind, GE
Lovig, T
Diep, CB
Meling, GI
Rognum, TO
Lothe, RA [1 ]
机构
[1] Norwegian Radium Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway
[2] Univ Oslo, Natl Hosp, Inst Forens Med, Oslo, Norway
[3] Univ Hosp Akershus, Dept Surg, Akershus, Norway
来源
NEOPLASIA | 2005年 / 7卷 / 02期
关键词
WNT signaling; colorectal cancer; genomic instability; mutation; hypermethylation;
D O I
10.1593/neo.04448
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 aneuplold 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.
引用
收藏
页码:99 / 108
页数:10
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