TY - JOUR
T1 - Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development
AU - Weren, Robbert D A
AU - Venkatachalam, Ramprasath
AU - Cazier, Jean-Baptiste
AU - Farin, Henner F
AU - Kets, C Marleen
AU - de Voer, Richarda M
AU - Vreede, Lilian
AU - Verwiel, Eugène T P
AU - van Asseldonk, Monique
AU - Kamping, Eveline J
AU - Kiemeney, Lambertus A
AU - Neveling, Kornelia
AU - Aben, Katja K H
AU - Carvajal-Carmona, Luis
AU - Nagtegaal, Iris D
AU - Schackert, Hans K
AU - Clevers, Hans
AU - van de Wetering, Marc
AU - Tomlinson, Ian P
AU - Ligtenberg, Marjolijn J L
AU - Hoogerbrugge, Nicoline
AU - Geurts van Kessel, Ad
AU - Kuiper, Roland P
N1 - © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
PY - 2015/6
Y1 - 2015/6
N2 - 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.
AB - 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.
KW - Adenomatous Polyposis Coli/genetics
KW - Adult
KW - Case-Control Studies
KW - Chromosomes, Human, Pair 9/genetics
KW - Colorectal Neoplasms/genetics
KW - DNA Copy Number Variations/genetics
KW - Epithelial Cells/metabolism
KW - Female
KW - Gene Deletion
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Germ-Line Mutation/genetics
KW - Heterozygote
KW - Humans
KW - Male
KW - Middle Aged
KW - Neoplasm Recurrence, Local/genetics
KW - Open Reading Frames/genetics
KW - Tumor Suppressor Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=84929277252&partnerID=8YFLogxK
U2 - 10.1002/path.4520
DO - 10.1002/path.4520
M3 - Article
C2 - 25712196
SN - 0022-3417
VL - 236
SP - 155
EP - 164
JO - The Journal of pathology
JF - The Journal of pathology
IS - 2
ER -