Frequency of hemochromatosis gene (HFE) mutations in Russian healthy women and patients with estrogen-dependent cancers

Abstract

Possible association between the C282Y and H63D mutations in the HFE gene and estrogen-dependent cancer risk was assessed. Genotyping was performed using PCR amplification followed by digestion of products with specific restrictases. In a population of 260 healthy women (permanent residents of the southwest European Russia), mutant allele frequencies at the C282Y and H63D sites were evaluated as 3.3 and 16.3%, respectively. In patients with breast, ovarian, and endometrial cancer, C282Y frequencies were also low (1.0, 1.3, and 3.8%, respectively), and no cancer risk associated with the C282Y mutation was found. Odds ratios for breast cancer risk associated with the H63D mutation increased significantly with age: 0.5 in women below 48 years old, 1.0 in a range of 48-57 years, and 4.4 in older women (P(trend)=0.002). The latter value was statistically significant (95% CI, 1.4-14.1), indicating that women bearing the H63D mutation may be at an increased breast cancer risk at an age above 57 years. Preliminary results obtained in patients with two other estrogen-dependent malignancies revealed the same tendency to OR increase with age in ovarian cancer patients (P(trend)=0.008), but no age-related OR differences in endometrial cancer patients.

HFEC282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for Chronic Myeloproliferative Disease

“…Heterozygous HFE carriership is associated with moderately increased iron parameters, and therefore, it has been suggested to be a genetic modifier of several clonal disorders (solid tumors and hematologic malignancies). Previous association studies regarding common HFE genetic variants in relation with susceptibility for solid tumors such as colon cancer (7,8,(14)(15)(16)(17), or breast cancer (9)(10)(11)18), are rather conflicting. HFE associations were investigated in hematologic malignancies as well.…”

“…Although HFE-related hemochromatosis is inherited in a recessive manner, heterozygous carriers were shown to have elevated iron parameters (serum iron and ferritin levels, transferrin saturation) without progressive iron overload (2)(3)(4)(5)(6). Heterozygous HFE carriership has been implicated as a risk factor for several clonal disorders such as hematologic malignancies and solid tumors (1,(7)(8)(9)(10)(11)(12). Transferrin receptor (TFR) is also a key element of the regulation of iron homeostasis.…”

“…The S142G variant of TFR was reported to influence cancer susceptibility (colon, breast, myeloma) in combination with distinct HFE genotypes (13). The effects of iron homeostasis, and HFE and TFR genotypes were extensively studied in several solid tumors even in large patient cohorts (7)(8)(9)(10)(11)(12)(14)(15)(16)(17)(18)), but only a few studies with small patient cohorts tested the potential role of HFE in chronic myeloproliferative disorders (CMPD), a clonal disorder of the main iron using tissue of the body (19)(20)(21).…”

Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis

“…17 At these sites, in addition to its independent role as a proxidant, high levels of free iron may accentuate the effects of other carcinogenic agents, such as estradiol, ethanol and ionizing radiation. 18 Studies on the association of HFE mutations and breast cancer risk have led to contradictory results, with some studies finding a positive association for both the C282Y 19-21 and H63D 22,23 mutations, while others reporting no association with either mutation. 24 In contrast, there is a surprising lack of information whether HFE mutations may be associated with other estrogen-dependent cancers, such as ovarian cancers.…”

Body iron stores and breast cancer risk in female atomic bomb survivors

“…(10) Recently, studies have appeared that have focused on breast cancer in particular and offer support for elevated dietary iron intake and ⁄ or body iron stores as a risk factor. (11)(12)(13)(14) Other studies have examined mutations in the hemochromatosis gene HFE and breast cancer risk (15,16) based on the idea that a diet high in iron would be particularly disadvantageous to those people carrying these mutations because increased iron absorption would lead to oxidative stress in mammary tissue from excess tissue iron. (17,18) Even though HFE mutations are very rare in Japan, (19) other genetic variants involved in iron absorption from the diet and ⁄ or physiological processing undoubtedly exist, although they have not yet been discovered.…”