title: Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.
abstract: OBJECTIVE
  Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
  
  
  METHODS
  We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
  
  
  RESULTS
  Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).
  
  
  CONCLUSIONS
  In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. upeters@fhcrc.org
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mesh_terms: D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D056742:Cyclin D2 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D007797:Laminin / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018570:Risk Assessment; D017678:Sex Distribution; D020825:T-Box Domain Proteins / Q000235:genetics
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; D004268:DNA-Binding Proteins; D007797:Laminin; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human; C089141:laminin gamma 1