title: Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer ?
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: UMR-S Inserm 490, Laboratoire de Toxicologie Moléculaire, Université René Descartes-Paris V, 75006 Paris, France. Sophie.Gad@biomedicale.univ-paris5.fr
authors.forename: Sophie
authors.initials: S
authors.lastname: Gad
authors.forename: David
authors.initials: D
authors.lastname: Teboul
authors.forename: Astrid
authors.initials: A
authors.lastname: Lièvre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goasguen
authors.forename: Anne
authors.initials: A
authors.lastname: Berger
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000368:Aged; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D002892:Chromosomes, Human, Pair 22; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C473750:CBY1 protein, human; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D012334:RNA, Neoplasm; D015534:Trans-Activators; D051176:beta Catenin