HFE gene mutations in susceptibility to childhood leukemia: HuGE review

Abstract

The hereditary hemochromatosis (HHC) gene, HFE on chromosome 6p21.3, encodes a protein involved in iron homeostasis. HFE mutations have low penetrance with a mild effect on serum iron levels. Animal, twin, and population studies have shown that carrier state for C282Y can increase iron levels. A proportion of heterozygotes show slightly elevated serum iron levels. Increased serum iron has been suggested to increase the risk for oxidative damage to DNA. Epidemiologic studies established a correlation between iron levels and cancer risk.Case-control studies have reported associations between HFE mutations C282Y/H63D and several cancers, some of which in interaction with the transferrin receptor gene TFRC or dietary iron intake. Increased cancer risk in C282Y carriers is likely due to higher iron levels in a multifactorial setting. In childhood acute lymphoblastic leukemia

Examination of gender effect in birth weight and miscarriage associations with childhood cancer (United Kingdom)

“…One other growth factor for both fetal [45,46] and cancer cell growth [47] is iron. The HFE gene shows a replicated association with childhood ALL in boys only [26], which is likely to be due to the effect of this mutation on body iron content [48]. Iron excess is also linked with gestational diabetes [49] and recently, an HFE association in gestational diabetes has been reported [50].…”

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

“…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).…”

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

“…The hereditary hemochromatosis gene, HFE, has shown multiple associations with cancer susceptibility [1][2][3][4][5][6][7], including risk for childhood acute lymphoblastic leukemia (ALL) [8], which has been replicated [9]. In multiple cancers [1,2], including childhood ALL [9], the association of HFE variants with cancer risk gets stronger in interaction with a polymorphism in the transferrin receptor gene (TFRC).…”