TY - JOUR
T1 - Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
AU - Hes, Frederik J.
AU - Ruano, Dina
AU - Nieuwenhuis, Marry
AU - Tops, Carli M.
AU - Schrumpf, Melanie
AU - Nielsen, Maartje
AU - Huijts, Petra E. A.
AU - Wijnen, Juul T.
AU - Wagner, Anja
AU - Gomez Garcia, Encarna B.
AU - Sijmons, Rolf H.
AU - Menko, Fred H.
AU - Letteboer, Tom G. W.
AU - Hoogerbrugge, Nicoline
AU - Harryvan, Jan
AU - Kampman, Ellen
AU - Morreau, Hans
AU - Vasen, Hans F. A.
AU - van Wezel, Tom
PY - 2014/1
Y1 - 2014/1
N2 - Background Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. Methods We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). Results We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. Conclusions These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
AB - Background Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. Methods We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). Results We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. Conclusions These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
KW - Cancer: colon
KW - Clinical genetics
KW - Genetic screening
KW - counselling
U2 - 10.1136/jmedgenet-2013-102000
DO - 10.1136/jmedgenet-2013-102000
M3 - Article
C2 - 24253443
SN - 0022-2593
VL - 51
SP - 55
EP - 60
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 1
ER -