Gender and plasma iron biomarkers, but not HFE gene mutations, increase the risk of colorectal cancer and polyps

Castiella, Agustín; Múgica, Fernando; Zapata, Eva; Zubiaurre, Leire; Iribarren, Arantxa; Juan, MaDolores de; Alzate, Luis; Gil, Inés; Urdapilleta, Gregorio; Otazua, Pedro; Emparanza, José Ignacio

doi:10.1007/s13277-015-3406-2

Cited by 11 publications

(3 citation statements)

References 25 publications

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“…Body iron stores and dietary iron intake have both been positively correlated with risk of colon cancer in some studies [19][20][21] . Relevant to the current study, plasma iron biomarkers and gender, rather than HFE gene mutations, were found to increase the risk of colorectal cancer and the development of polyps in a cohort of patients 22 . Consequently, multivariate risk factors could potentially contribute to colorectal cancer and Dcytb SNP rs10455 is a candidate polymorphism that could be screened in colon cancer patients.…”

Section: Strikingly Davies Et Al Reported a Positive Correlation Besupporting

confidence: 52%

Duodenal cytochrome b (Cybrd1) ferric reductase functional studies in cells

2017

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Dietary non-heme ferric iron is reduced by the ferric reductase enzyme, duodenal cytochrome b (Dcytb), before absorption by the divalent metal transporter 1 (DMT1). A single nucleotide polymorphism (SNP rs10455 mutant) that is located in the last exon of the Dcytb gene was reported in C282Y haemochromatosis HFE subjects. The present work therefore investigated the phenotype of this mutant Dcytb in Chinese hamster ovary (CHO) cells. These cultured cells were transfected with either wild type (WT) or the SNP vector plasmids of Dcytb. Ferric reductase assays were performed in Dcytb transgenic CHO cells using the ferrozine spectrophometric assay protocol. The Dcytb SNP rs10455 showed a gain-of-function capability since ferric reductase activity increased significantly (p < 0.01) in the transgenic cells. Varying ferric reductase activity was found when CHO cells were pretreated with modulators of Dcytb protein expression. Although ferric reductase in endogenous CHO cells increased with deferoxamine or CoCl, iron loading with ferric ammonium citrate (FAC) had the opposite effect. Taken together, the study reveals a gain-of-function phenotype for Dcytb rs10455 mutation that could be a putative modifier of colorectal cancer risk, with attendant variability in penetrance among human HFE C282Y homozygotes.

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Section: Strikingly Davies Et Al Reported a Positive Correlation Besupporting

confidence: 52%

Duodenal cytochrome b (Cybrd1) ferric reductase functional studies in cells

2017

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“…physical activity, obesity, smoking and alcohol consumption are closely associated with colorectal cancer (79). The correlation between excess iron and colorectal cancer risk has been examined in numerous previous studies (80)(81)(82), and iron overload associated with the H63D mutation and C282Y in HFE may increase the risk for developing colorectal cancer (83)(84)(85).…”

Section: Iron and Various Cancersmentioning

confidence: 99%

Iron metabolism and its contribution to cancer (Review)

et al. 2019

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Iron is an essential element for biological processes. Iron homeostasis is regulated through several mechanisms, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Iron has dual properties, which may facilitate tumor growth or cell death. Cancer cells exhibit an increased dependence on iron compared with normal cells. Macrophages potentially deliver iron to cancer cells, resulting in tumor promotion. Mitochondria utilize cellular iron to synthesize cofactors, including heme and iron sulfur clusters. The latter is composed of essential enzymes involved in DNA synthesis and repair, oxidation-reduction reactions, and other cellular processes. However, highly increased iron concentrations result in cell death through membrane lipid peroxidation, termed ferroptosis. Ferroptosis, an emerging pathway for cancer treatment, is similar to pyroptosis, apoptosis and necroptosis. In the present review, previous studies on the physiology of iron metabolism and its role in cancer are summarized. Additionally, the significance of iron regulation, and the association between iron homeostasis and carcinogenic mechanisms are discussed. Contents 1. Introduction 2. Iron absorption 3. Iron distribution and excretion 4. Iron and various cancers 5. Mechanisms of iron-mediated proliferation of tumor cells 6. Ferroptosis: Iron-dependent cancer cell death 7. Conclusions

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“…After the introduction of HFE genotyping in 1996, 20 similar cohort studies have been performed on HFE mutation carriers with or without clinical HH, but the results regarding the risk of extrahepatic malignancies are conflicting, which could possibly be attributed to differences in why the included populations were sampled for HFE (e.g. asymptomatic blood donors vs. targeted testing in symptomatic individuals) 16,17,21‐26 . Associations of HFE mutations have also been made with non‐malignant diseases such as type 2 diabetes (T2D), 8 Parkinson’s disease 27,28 and osteoarthritis 29,30 …”

Section: Introductionmentioning

confidence: 99%

Morbidity, risk of cancer and mortality in 3645 HFE mutations carriers

Hagström

Ndegwa

Jalmeus

et al. 2021

Liver International

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Background & Aims Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra‐hepatic diseases, especially breast and colorectal cancer. Here we investigated long‐term outcomes of Swedish patients with HFE mutations. Methods We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinson’s disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes. Results Median age at diagnosis was 52 years, 44% were females. During a mean follow‐up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver‐related outcomes were rare, with a cumulative incidence of <1%. Conclusions Individuals found to be HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed.

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Gender and plasma iron biomarkers, but not HFE gene mutations, increase the risk of colorectal cancer and polyps

Cited by 11 publications

References 25 publications

Duodenal cytochrome b (Cybrd1) ferric reductase functional studies in cells

Duodenal cytochrome b (Cybrd1) ferric reductase functional studies in cells

Iron metabolism and its contribution to cancer (Review)

Morbidity, risk of cancer and mortality in 3645 HFE mutations carriers

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