Tumor necrosis factor-related genes and colon and rectal cancer

Tumor necrosis factor-α (TNF) is a promoter of inflammation. Genes in the TNF pathway include tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNF receptor-associated factor 2 (TRAF2), mitogen activated protein kinase 8 (MAPK8), 14 (MAPK14), and mitogen activated protein kinase kinase kinase 7 (MAP3K7), nuclear factor of activated-T-5 (NFAT5) cells and NFAT activated protein with ITAM motif 1 ﹛NFAM1). Data from population-based studies of colon cancer (cases=1,555; controls=1,956) and rectal cancer (cases=754; controls=959) were used. We observed that MAP3K7 rs13208824 was associated with reduced colon cancer risk (OR 0.83, 95% CI 0.71, 0.98 dominant model), TNF rs1800630 was associated with an increased colon cancer risk (OR 1.19 95% CI 1.03, 1.38 for CA/AAvsCC), and TNFRSF1A rs4149570 was associated with reduced risk (OR 0.79 95% CI 0.64, 0.96 TTvsGG). For rectal cancer MAPK8 rs10508901 was associated with increased risk (OR 1.45 95% CI 1.05, 1.99 AA vs CC/CA; NFAT5 (rs12447326 and rs16959025) was associated with a 40% reduced risk for the recessive model. Aspirin/NSAID interacted with MAP3K7 (colon cancer) and with MAPK14, NFAT5, and TRAF2 (rectal cancer); smoking cigarettes interacted with NFAM1 and NFAT2 (colon cancer) and MAPK8, NFAT5, and TNFRSF1A (rectal cancer); BMI interacted with NFAM1 and NFAT5 (colon cancer) and with MAPK8 and TNFRSF1A (rectal cancer). A genotype summary score showed a threefold increased risk of dying with higher mutational load. Although few independent associations were detected, aspirin/NSAID, cigarette smoking, and BMI influenced genes in this pathway. These data suggest pathways through which TNF-signaling operates.