TY - JOUR
T1 - Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia
AU - Schubert, Stephanie A.
AU - Ruano, Dina
AU - Elsayed, Fadwa A.
AU - Boot, Arnoud
AU - Crobach, Stijn
AU - Sarasqueta, Arantza Farina
AU - Wolffenbuttel, Bruce
AU - Van Der Klauw, Melanie M.
AU - Oosting, Jan
AU - Tops, Carli M.
AU - Van Eijk, Ronald
AU - Vasen, Hans Fa
AU - Vossen, Rolf H.A.M.
AU - Nielsen, Maartje
AU - Castellví-Bel, Sergi
AU - Ruiz-Ponte, Clara
AU - Tomlinson, Ian
AU - Dunlop, Malcolm G.
AU - Vodicka, Pavel
AU - Wijnen, Juul T.
AU - Hes, Frederik J.
AU - Morreau, Hans
AU - De Miranda, Noel F.C.C.
AU - Sijmons, Rolf H.
AU - Van Wezel, Tom
N1 - Funding Information: This publication is supported by COST Action BM1206 and MSMT LD14050. This study was funded by grants from the Dutch Digestive Foundation (MLDS FP13-13), Dutch Cancer Society (KWF UL2010-4656), Stichting Sasha Swarttouw-Hij-mans and Leids Universiteits Fonds/ Gratama Stichting. This work was further supported by grants from Fondo de Investiga-ción Sanitaria/FEDER (14/00173, 14/00230), Fundación Cientí-fica de la Asociación Española contra el Cáncer (GCB13131592CAST), Catalan Tumour Bank Network (Pla Director d’Oncologia, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalunya, 2014SGR255). We are sincerely grateful to the Biobank of Hospital Clínic-IDIBAPS for technical help. The work was carried out in part at the Esther Koplowitz Centre and FPGMX. CIBERehd and CIBERER are funded by the Instituto de Salud Carlos III. We acknowledge core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/ 09/Z) and the Oxford NIHR Biomedical Research Centre. We thank Rashmi Dibipsersat, Nesli Ozcelik, Melanie Schrumpf and Brendy van den Akker for their technical support. Publisher Copyright: © 2017 Cancer Research UK. All rights reserved.
PY - 2017/9/5
Y1 - 2017/9/5
N2 - Background: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders.Methods: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level.Results: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues.Conclusions: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.
AB - Background: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders.Methods: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level.Results: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues.Conclusions: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.
UR - http://www.scopus.com/inward/record.url?scp=85028836164&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/bjc.2017.240
DO - https://doi.org/10.1038/bjc.2017.240
M3 - Article
C2 - 28742792
SN - 0007-0920
VL - 117
SP - 876
EP - 884
JO - British journal of cancer
JF - British journal of cancer
IS - 6
ER -