Table 2. Genes Associated with a High Susceptibility of Colorectal Cancer continued...
A large GWAS was performed using tagSNPs in a total of 10,731 CRC cases and 10,961 controls from eight centers to identify and enrich for CRC susceptibility alleles. In addition to the previously reported 8q24, 15q13, and 18q21 CRC risk loci, two previously unreported associations at 10p14 (P = 2.5 × 10-13) and 8q23.3 (P = 3.3 × 10-8) were identified. The 8q23.3 locus tags a plausible causative gene, EIF3H (OMIM). The authors of this study estimated that the loci identified account for approximately 3% to 4% of the excess familial CRC risk but that a high proportion of the population would be carriers of at-risk genotypes. They estimated that 3% of individuals may carry seven or more deleterious alleles. The authors concluded that their data are compatible with a polygenic model in which individual alleles, each exerting a small effect, combine either additively or multiplicatively to produce much larger risks in carriers of multiple risk alleles.
A GWAS using 555,510 SNPs in 14,500 cases of CRC and 13,294 controls from seven different centers revealed a previously unreported association on 11q23 (odds ratio [OR], 1.1; P = 5.8 × 10-10) and replicated susceptibility loci at 8q24 (OR, 1.19; P = 8.6 × 10-26) and 18q21 (OR, 1.2; P = 7.8 × 10-28). Furthermore, the authors were unable to identify causative coding sequence variants in any of the candidate genes at 8q24 (POU5F1P1, HsG57825, and DQ515897) or 18q21 (SMAD7). The variants identified are common in the general population, with risk-allele frequencies in populations of European ancestry of 0.29, 0.37, and 0.52, respectively. Carrying all six possible risk alleles yielded an estimated OR of 2.6 (95% confidence interval [CI], 1.75-3.89) for CRC.
A meta-analysis of GWAS data obtained from the two studies above (the combined dataset analyzed contained 38,710 polymorphic SNPs in 2,024 cases and 2,092 controls) revealed four additional susceptibility loci. In addition to six loci identified in previous GWAS (8q23, 8q24, 10p14, 11q23, 15q13, and18q21), the following four new loci were identified:
- Two SNPs linked to a 38 kilobase (kb) region on 20p12.3 [two SNPs: (i) combined OR, 1.12; 95% CI, 1.08-1.16; P = 2.0 × 10-10 and (ii) combined OR, 1.12; 95% CI, 1.08-1.17; P = 2.1 × 10-10] lacking genes or predicted protein-encoding transcripts;
- 14q22.2 (combined OR, 1.11; 95% CI, 1.08-1.15; P = 8.1 × 10-10) in a region 9.4kb from the transcription start site of the BMP4 gene;
- 19q13.1 [two SNPs: (i) combined OR, 0.87; 95% CI, 0.83-0.91; P = 4.6 × 10-9 and (ii) combined OR, 0.89; 95% CI, 0.85-0.93; P = 2.2 , 10-7], which lies within the Rho GTPase binding protein 2 (RHPN2) gene; and
- 16q22.1 (combined OR, 0.91; 95% CI, 0.89-0.94; P = 1.2 × 10-8), which lies within intron 1 of the E-cadherin (CDH1) gene.