%0 Journal Article
%T Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci
%A Iina Niittym£¿ki
%A Sari Tuupanen
%A Yilong Li
%A Heikki J£¿rvinen
%A Jukka-Pekka Mecklin
%A Ian PM Tomlinson
%A Richard S Houlston
%A Auli Karhu
%A Lauri A Aaltonen
%J BMC Medical Genetics
%D 2011
%I BioMed Central
%R 10.1186/1471-2350-12-23
%X Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions.No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC.The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered.Ten chromosomal loci have thus far been shown to modestly increase colorectal cancer (CRC) risk, based on genome-wide association studies (GWASs) [1-9]. The tagging single-nucleotide polymorphisms (SNPs) with the strongest association signal in each locus were rs6983267 at 8q24 [1-3], rs4939827 at 18q21 [4], rs4779584 at 15q13 [5], rs16892766 at 8q23 [6], rs10795668 at 10p14 [6], rs3802842 at 11q23 [7,8], rs4444235 at 14q22 [9], rs9929218 at 16q22 [9], rs10411210 at 19q13 [9], and rs961253 at 20p12 [9]. Each of the ten loci independently predispose to CRC with allelic odds ratios (ORs) of <1.3 and risk allele frequencies range between 7-90% in the general population [10].GWASs are based on genotyping SNPs which tag linkage disequilibrium (LD) blocks in the genome, thus capturing a high proportion of common genetic variation. Hence, usually the associating
%U http://www.biomedcentral.com/1471-2350/12/23