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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.

Original publication

DOI

10.1002/path.4520

Type

Journal article

Journal

J Pathol

Publication Date

06/2015

Volume

236

Pages

155 - 164

Keywords

FOCAD, cancer predisposition, copy number variation, gene expression, polyposis and colorectal cancer, Adenomatous Polyposis Coli, Adult, Case-Control Studies, Chromosomes, Human, Pair 9, Colorectal Neoplasms, DNA Copy Number Variations, Epithelial Cells, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, Heterozygote, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Open Reading Frames, Tumor Suppressor Proteins