Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability.
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.
Thorstensen
Lin
L
Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
Lind
Guro E
GE
Løvig
Tone
T
Diep
Chieu B
CB
Meling
Gunn I
GI
Rognum
Torleiv O
TO
Lothe
Ragnhild A
RA
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060466:Axin Protein; D014408:Biomarkers, Tumor / Q000378:metabolism*; D055511:CCN Intercellular Signaling Proteins; D015820:Cadherins / Q000235:genetics; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011003:Ploidies; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051153:Wnt Proteins; D051176:beta Catenin
C491761:AXIN2 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D014408:Biomarkers, Tumor; D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human