Hemochromatosis gene (HFE) mutations and cancer risk
Authors: Silvia Fargion, Luca Valenti, Anna Ludovica Fracanzani
Journal: Hepatology (2010)

The possible role of iron as a causative factor in cancer development has been debated for a long time, based on often-contrasting results obtained in animal models and on clinical studies that are frequently hampered by the inclusion of a limited number of subjects. The rationale that makes iron a potential carcinogen is based on the capability of this metal to induce oxidative stress by catalyzing hydroxyl radical formation through the Fenton reaction. Iron-catalyzed oxidative stress causes lipid peroxidation and protein modification, DNA damage with consequent promotion of mutagenesis, and leads to the depletion of antioxidant defenses. These properties are typical of transition metals, of which iron is the most frequently represented in biological systems, the one for which there is more direct evidence of a relationship with tissue damage, and whose concentration is more often increased in pathophysiological conditions characterized by genetic or secondary deregulation of iron homeostasis, so that the term "ferrotoxic diseases" has been coined.1 In addition, iron is an essential cofactor for cancer growth. At the cellular level, deregulation of cellular iron metabolism contributes to the malignant phenotype induced by oncogene expression. At the same time, alterations in iron homeostasis progressively determine intracellular iron accumulation during multistep carcinogenesis. Hence, iron chelators are under study as potential antineoplastic drugs.2 However, the elucidation of the complex effects of iron on the expression of molecules involved in cell cycle control remains in its infancy.3 A simplified model of iron-induced carcinogenesis is depicted in Fig. 1. A simplified overview illustrating the mechanisms involved in iron-mediated carcinogenesis.17 ERK, extracellular signal regulated kinase; p53, p53 tumor suppressor gene; SOD2, manganese superoxide dismutase; Tf-Fe, transferrin bound iron; Tf-R, transferrin receptor. The prototypical disease characterized by iron overload is hereditary hemochromatosis (HHC), which represents a well-established model of iron-induced toxicity and carcinogenesis. However, although it is generally accepted that patients with HHC-related cirrhosis are at increased risk of liver cancer, even in respect to properly matched patients with nonhemochromatosis liver diseases,4 results on extrahepatic cancers are contradictory.5 The results reported by Zacharski et al.6 in a randomized, controlled trial designed to test the hypothesis that iron reduction by phlebotomy would influence vascular outcomes in patients with peripheral arterial disease also support the carcinogenic role of iron. As a secondary endpoint, the authors demonstrated that patients who underwent phlebotomy had a lower risk of subsequent cancer, and those who developed cancer had lower cancer-specific deaths and deaths from any cause than patients in the control group. In contrast, Edgren et al.7 evaluated in a large series of more than 10,000 blood donors and a control group matched on sex, age, and country of residence, the relation between donation frequency, iron loss, and risk of cancer. The authors concluded that repeated blood donation was not associated with a different risk of cancer even if they observed a trend for decreased risk of liver, lung, and gastrointestinal cancers in subjects with highest blood donation rate. Other studies reported contrasting results on the increased risk of colon, rectal, breast, and prostate cancer among patients carrying hemochromatosis gene (HFE) mutations.8-10 Thus, despite a general feeling that iron, even in mild excess, may favor cancer occurrence, conclusive results have been until now very elusive. Further support for the promoting effect of iron on cancer comes from the recent demonstration that iron overload is frequent and deleterious in patients with acute leukemia or myelodysplastic syndrome undergoing myeloablative hematopoietic stem cell transplantation with a strong relationship between pretransplantation ferritin and survival.11 More recently, it was demonstrated that the effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload. Despite the presence of several confounders, which could influence the natural history of these diseases, these results could represent another example of the negative effect of iron on clinical history of cancer.12 In this issue of HEPATOLOGY, Osborne et al.13 present the results of a prospective cohort study, which enrolled almost 30,000 subjects born in Australia, New Zealand, the United Kingdom, and Ireland. All subjects were typed for the C282Y (cysteine-to-tyrosine substitution at residue 282) mutation of the HFE gene, and incident colon, prostate, and breast cancers—the more frequent tumors in this cohort—were assessed during 14 years of follow-up. The authors were able to demonstrate that male homozygotes for the C282Y mutation were at increased risk of colon cancer (hazard ratio = 2.28; range = 1.22-4.25), whereas female C282Y homozygotes were at increased risk for breast cancer (hazard ratio = 2.39; range = 1.24-4.61). In contrast, heterozygotes for this mutation, as well as C282Y/H63D compound heterozygotes, were not at increased risk. The novelty of this study is the large cohort of subjects enrolled and the long follow-up. Thus, for the first time results appear to unequivocally, even if indirectly, support the hypothesis that iron overload and/or homozygosity for the C282Y mutation plays a role in extrahepatic carcinogenesis. Of the 28,509 subjects genotyped for the C282Y mutation, only 193 (corresponding to 0.64%) were found to be C282Y homozygotes. Unfortunately, in this study, biochemical evaluation of iron status was not available, thus making it impossible to rule out whether, independent of the iron status, the C282Y HFE mutation may be associated with other genes facilitating cancer occurrence. However, the same group had previously demonstrated that the majority of C282Y homozygotes (82% of males and 65% of females) have increased ferritin, even if only 28% of males and 1% of females will develop an iron-related disease by the age of 65 years.14, 15 Thus, although the penetrance of C282Y homozygosity is low for the clinical manifestations of HHC, it is certain that the large majority of subjects with this genotype will have some amount of iron excess late in their life. The article by Osborne et al. will have a large impact on the readers because, despite the generally accepted concept that the C282Y homozygosis confers only a genetic predisposition to develop HHC but host-related or acquired factors are needed to manifest clinically as disease, the identification of an increased risk of cancer in subjects with this genotype, even in the absence of clinically overt iron overload, will prompt a more careful evaluation of cancer risk. Thus, after a first phase in which C282Y homozygotes were considered to be affected by HHC and a second phase in which the acknowledgment of the low penetrance of C282Y homozygosis on liver disease made population screenings inadvisable, we are entering a new era in which C282Y homozygosis could be looked at as a genetic risk condition for cancer. Prevalence of homozygosis for the C282Y mutation varies in Caucasians between 3% and 12% according to geographical origin. This implies that a large number of subjects may be at increased risk of cancer. Although it cannot be completely ruled out that other mechanisms (i.e., linkage disequilibrium with other genetic variants at risk on chromosome 6p)16 might explain the association between C282Y homozygosis and risk of cancer, the iron hypothesis seems to be the most promising. Interestingly, our group recently studied the molecular pathways underpinning iron-driven carcinogenesis, and demonstrated that iron regulates the oncogene MDM2 (murine double minute 2), a regulator of p53, influencing p53 activity and hepatic carcinogenesis. In patients with liver disease, we showed that a MDM2 promoter polymorphism associated with higher MDM2 expression and inhibition of p53, influenced the risk of developing HCC in patients with liver cirrhosis due to HHC as well as in patients with cirrhosis and iron overload not related to HHC.17 These data suggest that other genetic factors regulating the biological response to iron-induced damage, such as MDM2 or superoxide dismutase 2 (SOD2),17, 18 may interact with HFE mutations in determining the risk of cancer, and that the simultaneous evaluation of these markers may further refine our ability to identify individuals at risk. Finally, the data by Osborne et al. might be extrapolated to a wider perspective in which not only C282Y homozygotes but also all subjects with any evidence of minor iron overload, possibly related to other inherited factors, should be considered to be at increased risk of colorectal and breast cancer and possibly other not-yet identified cancers. Consequently, iron therapy and iron depletion should be carefully evaluated on an individual basis. Additional, prospective, and adequately powered studies are required to test this hypothesis. C282Y, cysteine-to-tyrosine substitution at residue 282; HFE, hemochromatosis gene; HHC, hereditary hemochromatosis; MDM2, murine double minute 2; SOD2, superoxide dismutase 2.