The evidence that mutations in the HFE gene for hemochromatosis are associated with increased cancer risk is inconsistent. The Melbourne Collaborative Cohort Study is a prospective cohort study that commenced recruitment in 1990. Participants born in Australia, New Zealand, the United Kingdom, or Ireland (n ؍ 28,509) were genotyped for the HFE C282Y (substitution of tyrosine for cysteine at amino acid 282) variant. Incident cancers were ascertained from Australian cancer registries during an average of 14 years follow-up. Hazard ratios (HRs), confidence intervals (CIs), and P values were obtained from separate Cox regression analyses for colorectal, breast, and prostate cancers, all other solid cancers, and all cancers. Compared to those with no C282Y variant, C282Y homozygotes were at increased risk of colorectal cancer (HR ؍ 2.28; 95% CI ؍ 1.22, 4.25; P ؍ 0.01) and female C282Y homozygotes were at increased risk of developing breast cancer (HR ؍ 2.39; 95% CI ؍ 1.24, 4.61; P ؍ 0.01), but male C282Y homozygotes were not at increased risk for prostate cancer (HR ؍ 0⅐96; 95% CI ؍ 0⅐43, 2⅐15; P ؍ 0.92). C282Y/H63D compound heterozygotes were not at increased risk for colorectal cancer (HR ؍ 1.27; 95% CI ؍ 0.80, 2.01), breast cancer (HR ؍ 1.16; 95% CI ؍ 0.74, 1.84), or prostate cancer (HR ؍ 1.08; 95% CI ؍ 0.68, 1.70). Conclusion: HFE C282Y homozygotes have twice the risk of colorectal and breast cancer compared with those individuals without the C282Y variant. (HEPATOLOGY 2010;51:1311-1318.) See Editorial on Page 1119.
T he essential trace element iron can be carcinogenic through a variety of mechanisms including catalyzing the formation of mutagenic hydroxyl radicals, 1 suppression of the host immune response, 2 and by acting as an essential nutrient for proliferating tumor cells. 3 Hereditary hemochromatosis is an inherited disorder of iron overload characterized by inappropriately elevated intestinal iron absorption. In HFE-associated hereditary hemochromatosis, mutations in the HFE gene can impair synthesis of the master iron-regulatory protein hepcidin. Reduced hepcidin levels leads to increased release of iron from intestinal cells and macrophages, ele-Abbreviations: C282Y, substitution of tyrosine for cysteine at amino acid 282; CI, confidence interval; H63D, substitution of aspartic acid for histidine at amino acid 63; HFE, hemochromatosis protein; HR, hazards ratio.