Cancer cells require large amounts of micronutrients, particularly iron, for their rapid growth and frequent divisions. Cellular iron uptake is regulated by the transferrin receptor and the hemochromatosis protein (HFE) system. Two frequent mutations in the HFE gene, H63D and C282Y, are associated with hemochromatosis type I, an inherited iron overload disease and, possibly, with cancer. In this study, we evaluated the frequency of the H63D and C282Y mutations in a cohort of 677 consecutive cases of woman with gynecological pathologies. Cases included 80 women with tumor-free pathologies normal ovary (NOV), 124 with benign ovarian tumors (BOV), 96 with epithelial ovarian cancer (EOC) tumors of low malignant potential (LPM), 264 with invasive tumors of the ovary (TOV) and 113 with endometrial cancer. We found that the C282Y allele frequency in EOC patients was higher than that in the control NOV group (5.8% vs. 1.3%, p < 0.001) and was associated with an increased risk of ovarian cancer (OR = 4.88; 95% CI 1. 15-20.61; p = 0.018). The effect of the two HFE mutations on patient survival was also analyzed.Kaplan-Meier analyses did not find any significant association between the H63D allele and patient survival. However, EOC patients with at least one C282Y allele had a decreased overall survival compared to those with no C282Y allele (p = 0.001). These results indicate that the C282Y mutation may increase the risk of developing ovarian cancer and may be further associated with poor outcomes. Keywords CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptIron is an essential trace element that can be carcinogenic through a variety of mechanisms including acting as an essential nutrient for proliferating tumor cells, 1 catalyzing the formation of mutagenic hydroxyl radicals, 2 and by suppressing the host immune response. 3,4 In the past decades, several genes were identified as being central to the maintenance of iron homeostasis. 5 One such gene is HFE, a major histocompatibility class I-like (MHC-I-like) molecule, that, when mutated, may cause hereditary hemochromatosis (HH). 6 HH is a common genetic disorder in Caucasian populations that is characterized by high levels of iron absorption from diet, which results in the presence of high circulating iron levels and iron accumulation in the body. 7 As with other MHC-I molecules, HFE needs to associate with β2-microglobulin (β2m) for its appropriate expression at the cell surface. 8 The two most common mutations in HFE are C282Y, a guanine-to-adenine transition leading to a cysteine-to-tyrosine change and H63D, a cysteine-to-guanine transition causing a histidineto-aspartic acid change. 6 HFE associates with the major protein responsible for cellular iron uptake, namely the transferrin receptor (TfR), 9 also called CD71. The association of HFE with TfR at the cell surface lowers TfR affinity for the circulating iron-transporter transferrin, thereby limiting iron uptake and thus directly implicating HFE in the modulation of cellular iron level...