No evidence of increased risk of colorectal cancer in individuals heterozygous for the Cys282Tyr haemochromatosis mutation

Macdonald, Graeme A.; Tarish, J. H.; Vj, Whitehall; Sj, McCann; Mellick, George D.; Rl, Buttenshaw; Ag, Johnson; Young, Joanne; Leggett, Barbara A.

doi:10.1046/j.1440-1746.1999.02027.x

Cited by 33 publications

(25 citation statements)

References 17 publications

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“…When HFE mutations were considered separately, there was only a small, nonsignificant increased risk of colorectal cancer; in this respect therefore, our data support the earlier, negative findings (15,17,18). Our study also considered the colorectal cancer risk to an individual carrying both C282Y and H63D compound heterozygous mutations.…”

Section: Discussionsupporting

confidence: 89%

“…Other studies have found no link between any HFE mutation and risk of colorectal cancer. For example, Beckman et al (15) reported that genetic variants of HFE were not associated with increased risk of this disease or of multiple myeloma and breast cancer; two other studies found that heterozygosity for the C282Y mutation did not increase risk of colorectal cancer (17,18). Hence, it would seem that the higher overall statistically significant risk reported by Shaheen et al (19) may be a consequence of inclusion of the African American subjects in their study.…”

Section: Discussionmentioning

confidence: 99%

“…One study has suggested that whereas there was no association for HFE and TFR independently, individuals heterozygous or homozygous for the C282Y mutation and homozygous for the S142 allele had an increased risk of multiple myeloma, breast cancer, and colorectal cancer (15,16). The lack of association between HFE mutations, when considered in isolation, and colorectal cancer has been supported by two other investigations (17,18), although another study has found a modestly increased risk of colon cancer for carriers of any HFE mutation compared with subjects with no mutation (adjusted odds ratio [ To determine whether there is an increased risk of colorectal cancer in individuals carrying mutant HFE and TFR alleles, independently or as a combination, we established genotype frequencies of mutant alleles in a well-defined population with a family history of colorectal cancer and in a randomly selected control group. The use of cases with a family history increases the statistical power of the study compared with a set of unselected cases (20).…”

Section: Introductionmentioning

confidence: 99%

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Evidence for an Association between Compound Heterozygosity for Germ Line Mutations in the Hemochromatosis (HFE) Gene and Increased Risk of Colorectal Cancer

Robinson

Johnson

Rogers³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P observed = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation. (Cancer Epidemiol

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for an Association between Compound Heterozygosity for Germ Line Mutations in the Hemochromatosis (HFE) Gene and Increased Risk of Colorectal Cancer

Robinson

Johnson

Rogers³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Andrikovics

Meggyesi

Szilvási

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Iron metabolism has been implicated in carcinogenesis and several studies assessed the potential role of genetic variants of proteins involved in iron metabolism (HFE C282Y, TFR S142G) in different malignancies. Few reports addressed this issue with relation to chronic myeloproliferative disorders (CMPD). The aims of our study were (a) to examine the potential associations of CMPD development with genetic modifiers of iron metabolism in a large cohort of CMPD patients; (b) to examine associations of genetic variants of proteins involved in iron metabolism; and acquired JAK2 V617F mutation with clinical characteristics of CMPD. HFE C282Y was genotyped in 328 CMPD patients and 996 blood donors as controls, HFE H63D, and TFR S142G were tested in CMPD patients and 171 first time blood donors. JAK2 V617F mutation was tested in CMPD patients and in 122 repeated blood donors. Decreased C282Y allele frequency (allele frequency F 95% confidence interval) was found in the CMPD group (1.8% F 1.0%) compared with controls (3.4% F 0.8%; P = 0.048). TFR S142G allele frequency was reduced among V617F-negative CMPD patients (34.8% F7.6%) compared with controls (47.8% F 5.4%; P = 0.02). The frequency of JAK2 V617F was 75.9% (249 of 328) in the CMPD group. At presentation, elevated hemoglobin levels were found in V617F-positive patients compared with V617F-negative counterparts (P < 0.000). Vascular complications (26.6% versus 15.2%; P = 0.039) as well as female gender (57.4% versus 41.8%; P = 0.019) were more common in V617F-positive patients. We found that HFE C282Y might be associated with a protective role against CMPD. Because chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, HFE C282Y positivity may be a genetic factor influencing this effect. (Cancer Epidemiol Biomarkers Prev 2009;18(3):929 -34)

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HFE C282Y homozygotes are at increased risk of breast and colorectal cancer

et al. 2009

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The evidence that mutations in the HFE gene are associated with increased cancer risk is inconsistent. The Melbourne Collaborative Cohort Study is a prospective cohort study that commenced recruitment in 1990. Participants of born in Australia, New Zealand, the United Kingdom or Ireland (n = 28,509) were genotyped for the HFE C282Y variant. Incident cancers were ascertained from Australian cancer registries during an average of 14 years follow up. Hazard ratios, confidence intervals and p-values were obtained from separate Cox regression analyses for colorectal, breast and prostate cancers, all other solid cancers and all cancers. Compared with those with no C282Y variant, C282Y homozygotes were at increased risk of colorectal cancer (HR 2·28; 95% CI 1·22, 4·25; p = 0.01) and female C282Y homozygotes were at increased risk of developing breast cancer (HR 2·39; 95% CI 1·24, 4·61; p = 0.01) but male C282Y homozygotes were not at increased risk for prostate cancer (HR 0·96; 95% CI 0·43, 2·15; p = 0.92). C282Y/H63D compound heterozygotes were not at increased risk for colorectal cancer, (HR 1 27; 95% CI 0·80, 2·01); breast cancer, (HR 1·16; 95% CI 0·74, 1·84); or prostate cancer (HR 1·08; 95% CI 0·68, 1·70). Conclusion HFE C282Y homozygotes have twice the risk of colorectal and breast cancer compared with those without the C282Y variant.

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No evidence of increased risk of colorectal cancer in individuals heterozygous for the Cys282Tyr haemochromatosis mutation

Abstract: Heterozygosity for the Cys282Tyr mutation of HFE does not appear to be a risk factor for colorectal carcinoma.

Cited by 33 publications

References 17 publications

Evidence for an Association between Compound Heterozygosity for Germ Line Mutations in the Hemochromatosis (HFE) Gene and Increased Risk of Colorectal Cancer

Evidence for an Association between Compound Heterozygosity for Germ Line Mutations in the Hemochromatosis (HFE) Gene and Increased Risk of Colorectal Cancer

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

HFE C282Y homozygotes are at increased risk of breast and colorectal cancer

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