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Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development.

ABSTRACT: Heritable genetic variants can significantly affect the lifetime risk of developing cancer, including polyposis and colorectal cancer (CRC). Variants in genes currently known to be associated with a high risk for polyposis or CRC, however, explain only a limited number of hereditary cases. The identification of additional genetic causes is, therefore, crucial to improve CRC prevention, detection and treatment. We have performed genome-wide and targeted DNA copy number profiling and resequencing in early-onset and familial polyposis/CRC patients, and show that deletions affecting the open reading frame of the tumour suppressor gene FOCAD are recurrent and significantly enriched in CRC patients compared with unaffected controls. All patients carrying FOCAD deletions exhibited a personal or family history of polyposis. RNA in situ hybridization revealed FOCAD expression in epithelial cells in the colonic crypt, the site of tumour initiation, as well as in colonic tumours and organoids. Our data suggest that monoallelic germline deletions in the tumour suppressor gene FOCAD underlie moderate genetic predisposition to the development of polyposis and CRC.

SUBMITTER: Weren RD

PROVIDER: S-EPMC6681464 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development.

Weren Robbert D A RD Venkatachalam Ramprasath R Cazier Jean-Baptiste JB Farin Henner F HF Kets C Marleen CM de Voer Richarda M RM Vreede Lilian L Verwiel Eugène T P ET van Asseldonk Monique M Kamping Eveline J EJ Kiemeney Lambertus A LA Neveling Kornelia K Aben Katja K H KK Carvajal-Carmona Luis L Nagtegaal Iris D ID Schackert Hans K HK Clevers Hans H van de Wetering Marc M Tomlinson Ian P IP Ligtenberg Marjolijn J L MJ Hoogerbrugge Nicoline N Geurts van Kessel Ad A Kuiper Roland P RP

The Journal of pathology 20150326 2

Heritable genetic variants can significantly affect the lifetime risk of developing cancer, including polyposis and colorectal cancer (CRC). Variants in genes currently known to be associated with a high risk for polyposis or CRC, however, explain only a limited number of hereditary cases. The identification of additional genetic causes is, therefore, crucial to improve CRC prevention, detection and treatment. We have performed genome-wide and targeted DNA copy number profiling and resequencing ...[more]

PMID: 25712196

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Project description:BackgroundA 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.MethodsFirst, 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.ResultsLoss 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.ConclusionAs 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.

Dataset Information

Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development.

Publications

Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development.

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