WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite instability.
OBJECTIVE
Microsatellite instability (MSI) is the phenotype of colorectal carcinomas with defect mismatch repair. Genes with repetitive sequences within their coding regions are targets for mutations in these tumors. We have evaluated 2 novel candidate genes for potential involvement in development of MSI colorectal carcinomas and compared them with alterations in known target genes.


METHODS
The MSI status was determined by multiplex polymerase chain reactions (PCRs) of 5-17 markers in a Norwegian series of 275 colorectal carcinomas. All MSI tumors were analyzed for gene mutations using fluorescence PCR followed by capillary electrophoresis. Two novel candidate genes, WNT1-inducible signaling pathway protein 3 (WISP-3) and caspase-1, and 9 known target genes were analyzed.


RESULTS
Thirteen percent of the tumors were MSI-high (H) and 12% were MSI-low (L). Thirty-three of 37 MSI-H vs. 1 of 34 MSI-L tumors showed mutations in the target genes (P < 0.001). WISP-3 was mutated in 31% of the MSI-H tumors. The frequencies of frameshift mutations in the known target genes were comparable with other studies.


CONCLUSIONS
The relative high frequency of mutation, higher than those seen for other known target genes, the predicted truncation of the protein product, and the homology with WISP-1 and WISP-2, 2 proteins induced downstream of WNT1 signaling, strongly suggest WISP-3 as a novel target in development of MSI-H colorectal carcinomas.
Thorstensen
L
L
Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, 0310 Oslo, Norway.
Diep
C B
CB
Meling
G I
GI
Aagesen
T H
TH
Ahrens
C H
CH
Rognum
T O
TO
Lothe
R A
RA
D000368:Aged; D055511:CCN Intercellular Signaling Proteins; D002277:Carcinoma / Q000235:genetics*; D020170:Caspase 1 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018390:Gene Targeting; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D014407:Tumor Cells, Cultured
D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; D020170:Caspase 1