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Published on: May 10, 2019
Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer ?
Sophie Gad1, David Teboul, Astrid Lièvre
1UMR-S Inserm 490, Laboratoire de Toxicologie Moléculaire, Université René Descartes-Paris V, 75006 Paris, France. Sophie.Gad@biomedicale.univ-paris5.fr
Background:
A novel member of the Wnt signalling pathway, Chibby, was recently identified. This protein inhibits Wnt/beta-catenin mediated transcriptional activation by competing with Lef-1 (the transcription factor and target of beta-catenin) to bind to beta-catenin. This suggests that Chibby could be a tumour suppressor protein. The C22orf2 gene coding Chibby is located on chromosome 22, a region recurrently lost in colorectal cancer. Activation of the Wnt pathway is a major feature of colorectal cancer and occurs through inactivation of APC or activation of beta-catenin. All of this led us to analyse the possible implication of Chibby in colorectal carcinogenesis.
Methods:
First, 36 tumour and matched normal colonic mucosa DNA were genotyped with five microsatellite markers located on chromosome 22 to search for loss of heterozygosity. Then, mutation screening of the C22orf2 coding sequence and splice sites was performed in the 36 tumour DNA. Finally, expression of Chibby was analysed by quantitative RT-PCR on 10 patients, 4 with loss of heterozygosity (LOH) on chromosome 22.
Results:
Loss of heterozygosity involving the C22orf2 region was detected in 11 out of 36 patients (30%). Sequencing analysis revealed a known variant, rs3747174, in exon 5: T321C leading to a silent amino acid polymorphism A107A. Allelic frequencies were 0.69 and 0.31 for T and C variants respectively. No other mutation was detected. Among the 10 patients studied, expression analysis revealed that Chibby is overexpressed in 2 tumours and underexpressed in 1. No correlations were found with 22q LOH status.
Conclusion:
As no somatic mutation was detected in C22orf2 in 36 colorectal tumour DNA, our results do not support the implication of Chibby as a tumour suppressor in colorectal carcinogenesis. This was supported by the absence of underexpression of Chibby among the tumour samples with 22q LOH. The implication of other Wnt pathway members remains to be identified to explain the part of colorectal tumours without mutation in APC and beta-catenin.
Insights
Chibby protein does not appear to suppress colorectal cancer. Studies found no mutations in the C22orf2 gene and no correlation between Chibby expression and tumor development.
Area of Science:
- Molecular biology
- Cancer research
- Genetics
Background:
- Chibby, a Wnt pathway regulator, inhibits Wnt/beta-catenin signaling.
- Chibby's gene (C22orf2) is on chromosome 22, frequently lost in colorectal cancer.
- Wnt pathway activation is key in colorectal cancer development.
Purpose of the Study:
- Investigate Chibby's role in colorectal carcinogenesis.
- Analyze C22orf2 gene alterations and Chibby expression in colorectal tumors.
Main Methods:
- Genotyping for loss of heterozygosity (LOH) on chromosome 22.
- Mutation screening of the C22orf2 gene.
- Quantitative RT-PCR for Chibby expression analysis.
Main Results:
- LOH in the C22orf2 region found in 30% of tumors.
- A known silent variant (A107A) was identified; no other mutations.
- Chibby was overexpressed in 2 tumors, underexpressed in 1; no correlation with LOH.
Conclusions:
- No evidence supports Chibby as a tumor suppressor in colorectal cancer.
- Absence of Chibby underexpression in tumors with 22q LOH.
- Other Wnt pathway members may explain colorectal tumors with normal APC/beta-catenin.
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