Genome-wide interaction study with smoking for colorectal cancer risk identifies novel genetic loci related to tumor suppression, inflammation and immune response


 Background: Tobacco smoking is an established risk factor for colorectal cancer (CRC). However, genetically-defined population subgroups may have increased susceptibility to smoking-related effects on CRC. Methods: A genome-wide interaction scan was performed including 33,756 CRC cases and 44,346 controls from three genetic consortia. Results: Evidence of an interaction was observed between smoking status (ever vs never smokers) and a locus on 3p12.1 (rs9880919, p=4.58x10-8), with higher associated risk in subjects carrying the GG genotype (OR 1.25, 95%CI 1.20-1.30) compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, p=1.72x10-8) and 8q24.23 (rs7005722, p=2.88x10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR 1.12, 95%CI 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR 1.17, 95%CI 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower CRC risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Conclusions: Our study identified novel genetic loci that may modulate the risk for CRC of smoking status and intensity, linked to tumor suppression and immune response. Impact: These findings can guide potential prevention treatments.