Genetic Polymorphisms and Colorectal Cancer Risk
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 x 10-10) and replicated susceptibility loci at 8q24 (OR = 1.19; P = 8.6 x 10-26) and 18q21 (OR = 1.2; P = 7.8 x 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. It was estimated that carrying all six possible risk alleles yielded an 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 X 10-10 and (ii) combined OR = 1.12; 95% CI, 1.08-1.17; P = 2.1 X 10-10] lacking genes or predicted protein-encoding transcripts;
- 14q22.2 (combined OR = 1.11; 95% CI, 1.08-1.15, P = 8.1 X 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 X 10-9 and (ii) combined OR = 0.89; 95% CI, 0.85-0.93; P = 2.2 X 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 X 10-8), which lies within intron 1 of the E-cadherin (CDH1) gene.
No interactions between the loci were associated with an increased risk for CRC and the loci identified were estimated to collectively account for approximately 6% of the excess familial risk for CRC. The data analyses led the authors to conclude the following:
- The loci readily detectable through current GWAS are associated with modest effects (genotypic risks of approximately 1.2).
- The number of common variants explaining more than 1% of inherited risk is very low.
- Only a small proportion of heritability of any cancer can be explained by the currently identified loci.
- Of the common risk loci identified thus far, no significant epistatic effects were observed.