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 Ham
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 Fcc
AU - Sijmons, Rolf H
AU - van Wezel, Tom
PY - 2017/7/25
Y1 - 2017/7/25
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.British Journal of Cancer advance online publication: 25 July 2017; doi:10.1038/bjc.2017.240 www.bjcancer.com.
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.British Journal of Cancer advance online publication: 25 July 2017; doi:10.1038/bjc.2017.240 www.bjcancer.com.
KW - Journal Article
U2 - 10.1038/bjc.2017.240
DO - 10.1038/bjc.2017.240
M3 - Article
C2 - 28742792
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
ER -