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J Pathol. 2015 Jun;236(2):155-64. doi: 10.1002/path.4520. Epub 2015 Mar 26.

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

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Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
Wellcome Trust Centre for Human Genetics University of Oxford, UK.
Hubrecht Institute, University Medical Centre Utrecht, The Netherlands.
Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands.
Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, CA, USA.
Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Germany.


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.


FOCAD; cancer predisposition; copy number variation; gene expression; polyposis and colorectal cancer

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