title: 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.
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Robbert D A
authors.initials: RD
authors.lastname: Weren
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Ramprasath
authors.initials: R
authors.lastname: Venkatachalam
authors.affiliation: Wellcome Trust Centre for Human Genetics University of Oxford, UK.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, The Netherlands.
authors.forename: Henner F
authors.initials: HF
authors.lastname: Farin
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: C Marleen
authors.initials: CM
authors.lastname: Kets
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Richarda M
authors.initials: RM
authors.lastname: de Voer
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Lilian
authors.initials: L
authors.lastname: Vreede
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Eugène T P
authors.initials: ET
authors.lastname: Verwiel
authors.affiliation: Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: van Asseldonk
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Eveline J
authors.initials: EJ
authors.lastname: Kamping
authors.affiliation: Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.affiliation: Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.|Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands.
authors.forename: Katja K H
authors.initials: KK
authors.lastname: Aben
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, CA, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Carvajal-Carmona
authors.affiliation: Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.affiliation: Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Hubrecht Institute, University Medical Centre Utrecht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.affiliation: Wellcome Trust Centre for Human Genetics University of Oxford, UK.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Tomlinson
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.|Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Ad
authors.initials: A
authors.lastname: Geurts van Kessel
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C572579:FOCAD protein, human; D025521:Tumor Suppressor Proteins
keywords: FOCAD; cancer predisposition; copy number variation; gene expression; polyposis and colorectal cancer