title: Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci.
abstract: BACKGROUND
  Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Iina
authors.initials: I
authors.lastname: Niittymäki
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D022981:Allelic Imbalance / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019295:Computational Biology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics
chemical_list: D014157:Transcription Factors