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.
PY - 2015/6/1
Y1 - 2015/6/1
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 - cancer predisposition
KW - copy number variation
KW - FOCAD
KW - gene expression
KW - polyposis and colorectal cancer
UR - http://www.scopus.com/inward/record.url?scp=84929277252&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929277252&partnerID=8YFLogxK
U2 - 10.1002/path.4520
DO - 10.1002/path.4520
M3 - Article
C2 - 25712196
AN - SCOPUS:84929277252
VL - 236
SP - 155
EP - 164
JO - Investigative and Cell Pathology
JF - Investigative and Cell Pathology
SN - 0022-3417
IS - 2
ER -