Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis.
Whiffin N., Hosking FJ., Farrington SM., Palles C., Dobbins SE., Zgaga L., Lloyd A., Kinnersley B., Gorman M., Tenesa A., Broderick P., Wang Y., Barclay E., Hayward C., Martin L., Buchanan DD., Win AK., Hopper J., Jenkins M., Lindor NM., Newcomb PA., Gallinger S., Conti D., Schumacher F., Casey G., Liu T., Swedish Low-Risk Colorectal Cancer Study Group None., Campbell H., Lindblom A., Houlston RS., Tomlinson IP., Dunlop MG.
To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.