Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia.

0476876 - ÚEM 2018 RIV GB eng J - Journal Article
Schubert, S.A. - Ruano, D. - Elsayed, F.A. - Boot, A. - Crobach, S. - Sarasqueta, A.F. - Wolffenbuttel, B. - van der Klauw, M.M. - Oosting, J. - Tops, C.M. - van Eijk, R. - Vasen, H.F. - Vossen, R.H. - Nielsen, M. - Castellví-Bel, S. - Ruiz-Ponte, C. - Tomlinson, I. - Dunlop, M.G. - Vodička, Pavel - Wijnen, J.T. - Hes, F.J. - Morreau, H. - de Miranda, N.F. - Sijmons, R.H. - van Wezel, T.
Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia.
British Journal of Cancer. Roč. 117, č. 8 (2017), s. 1215-1223. ISSN 0007-0920. E-ISSN 1532-1827
R&D Projects: GA MŠMT(CZ) LD14050
Institutional support: RVO:68378041
Keywords : hereditary colorectal cancer * colorectal polyps * homozygosity mapping
OECD category: Biochemistry and molecular biology
Impact factor: 5.922, year: 2017

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.
Permanent Link: http://hdl.handle.net/11104/0276656