The risk of new‐onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants

Abstract

To investigate the association between mutation of HFE (the principal pathogenic gene in hereditary haemochromatosis) and risk of cancer, we conducted a meta‐analysis of all available case–control or cohort studies relating to two missense mutations, C282Y and H63D mutations. Eligible studies were identified by searching databases including PubMed, Embase and the ISI Web of Knowledge. Overall and subgroup analyses were performed and odds ratios (ORs) combined with 95% confidence intervals (CIs) were applied to evaluate the association between C282Y mutation, H63D mutation and cancer risk. Sensitivity and cumulative analyses were used to evaluate the stability of the results. A total of 36 eligible studies were included, comprising 13,680 cases and 73,348 controls. C282Y was significantly associated with elevated cancer risk in a recessive genetic model (OR: 1.991, 95% CI: 1.448–2.737). On subgroup analysis stratified by cancer type, statistically significantly increased cancer risks were found for breast cancer, colorectal cancer and hepatocellular carcinoma in a recessive model. When stratified by territory, a significantly increased risk of cancer was found in Oceanic populations in a recessive model and in Asian populations in an allele model and dominant model. H63D mutation did not significantly increase overall cancer risk in any genetic model. However, when, stratified by territory, an increased cancer risk was found in the Asian population in an allele and dominant. C282Y but not H63D mutation was related to elevated cancer risk. Further large‐scale studies considering gene–environment interactions and functional research should be conducted to further investigate this association.

Iron status in relation to cancer risk and mortality: Findings from a population‐based prospective study

“…Observations of such “ferrotoxic” effects of iron from basic science are paralleled by findings from observational studies among patients who suffer from hereditary hemochromatosis due to a genetic mutation in the hemochromatosis (HFE) gene. These patients show an augmented accumulation of iron in the liver and other tissues, and are thus at greater risk of developing hepatocellular carcinoma, and possibly also gastric, colon and breast cancer . A further line of evidence on potential carcinogenic effects of high iron status comes from a randomized clinical trial (RCT) indicating reduced risk of visceral malignancies and mortality among male patients with peripheral artery disease, who underwent phlebotomy, with substantial decreases in serum ferritin, the routine marker for excess iron …”

Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting

“…Notably, we found an excess of hemochromatosis risk genotype (HFE c.845G>A [p.Cys282Tyr] homozygotes) among CRCaffected case subjects (1.13%) compared to either polypsaffected or control groups, which each had a rate consis-tent with the population allele frequency in European ancestry individuals (MAF 4.96%). Hemochromatosis has been associated with excess risk of CRC; 23 however, this is not well known in the genetics community and is not included in most hemochromatosis review papers used by physicians. This finding warrants further estimation of the risk of cancer in individuals with hemochromatosis, including both risk and age of onset.…”

Iron Metabolism in Cancer Progression

“…Meta-analyses focusing on the issue of the association between cancer and HFE variants, reported conflicting results. In some meta-analysis, C282Y but not H63D variant was related to elevated cancer risk [52], including colorectal cancer [53] under recessive model (OR = 2.00, 95 % CI = 1.32-3.04), in Caucasians. The latter association was evident for studies concerning more than 500 cases.…”