Gastroenterology

Gastroenterology

Volume 121, Issue 6, December 2001, Pages 1275-1280
Gastroenterology

Rapid Communications
WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite instability,☆☆,

https://doi.org/10.1053/gast.2001.29570Get rights and content

Abstract

Background & Aims: 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.

GASTROENTEROLOGY 2001;121:1275-1280

Section snippets

Patients and tumor samples

The present study included 275 primary tumors from 273 Norwegian colorectal cancer patients: 252 patients from a consecutive series and 21 selected patients with tumors located in the right colon. From each of 24 primary tumors, 2 or more biopsy specimens were collected and totally 303 lesions were analyzed. Three patients satisfied the Amsterdam criteria for hereditary nonpolyposis colorectal cancer.22 All tumors were classified according to the World Health Organization recommendations.23 One

Results

MSI at 1 or more loci was found in 70 of 275 (25%) of the carcinomas. Forty-three biopsy specimens from 36 tumors were MSI-H, 34 biopsy specimens from 33 tumors were MSI-L, and 2 biopsy specimens from 1 tumor were MSI-H and MSI-L, respectively.

Among the 24 primary tumors with 2 or more biopsies performed, 7 contained biopsy specimens with MSI. Intratumor heterogeneity was observed in 2 of the 7 tumors. Both biopsy specimens from 1 of the tumors were MSI-H, but only 1 of them showed changes in

Discussion

The frequency of MSI-H tumors (13%) reported in the present study is within the range of previous studies.6, 30 The present study confirmed that alterations in BAT-25 and BAT-26 identify the tumors prone for mutations in downstream target genes.31

MSI intratumor heterogeneity was seen in 2 of the primary tumors with more than 1 biopsy specimen analyzed. This result is different from a previous report that observed MSI throughout all of the 4 investigated areas of 6 analyzed primary tumors.32

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  • Cited by (0)

    Supported by grants from the Norwegian Cancer Society (NCS).

    ☆☆

    Address requests for reprints to: Ragnhild A. Lothe, M.Sc., Ph.D., Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, 0310 Oslo, Norway. e-mail: [email protected]; fax: (47) 22934440.

    Dr. Thorstensen is a research fellow of the NCS.

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