Analysis of HFE and TFR2 gene mutations in patients with acute leukemia

There are increasing evidences regarding the association between iron overload and extra-hepatic malignancies. We studied the prevalence of 12 hereditary hemochromatosis (HH) gene mutations (C282Y, V53M, V59M, H63D, H63H, S56C, Q127H, E168Q, E168X, W169X and Q283P in the HFE gene and Y250X in the TFR2 gene) and its correlation with the iron status in 82 adult patients with acute leukemia (AL); 48 patients (58.5%) were affected by acute myeloid leukemia (AML) and 34 patients (41.5%) by acute lymphoblastic leukemia (ALL); 27 patients (32.9%) had at least one HH gene mutation (6 heterozygous for C282Y, 6 homozygous for H63D, 13 heterozygous for H63D and 2 heterozygous for S56C). Mean serum ferritin levels at diagnosis were increased (822.5+/-811.4 microg/L). However, there was no difference between patients positive or negative for the HH gene mutations. Similarly, we did not observe any statistically significant difference as far as iron status between AML and ALL patients. Our study does not support the evidence of an association between hemochromatosis gene mutations and iron overload in AL patients.     

Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients

Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero- and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population-based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(-2)A-->G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.     

Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer

Background: Iron is a pro-oxidant that may promote carcinogenesis. Mutations in the hemochromatosis (HFE) gene are associated with increased total body iron stores in some individuals. We assessed the risk of colon cancer among individuals with and without HFE gene mutations. METHODS: We performed a population-based, case-control study in North Carolina. Case patients with colon cancer and control subjects provided information on multiple environmental exposures, including total iron intake and nonsteroidal anti-inflammatory drug (NSAID) use. They also provided a venous blood sample, from which DNA was extracted, amplified, and subjected to diagnostic restriction enzyme mapping to detect two major HFE gene mutations, C282Y and H63D. Data were analyzed with Fisher's exact test and logistic regression. All statistical tests were two-sided. RESULTS: Thirteen hundred and eight subjects participated (475 case patients, 833 control subjects). The allele frequencies of the H63D and C282Y mutations were greater among case patients (0.11 and 0.046, respectively) than among control subjects (0.09 and 0.044, respectively; P =.14 and P =.85, respectively). When we controlled for age, race, sex, red meat consumption, NSAID use, and total iron intake, subjects with any HFE gene mutation were more likely to have colon cancer than subjects with no HFE gene mutations (adjusted odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.07 to 1.87). The magnitude of the effect was similar for both the H63D (adjusted OR = 1.44, 95% CI = 1.04 to 1.98) and C282Y mutations (adjusted OR = 1.39, 95% CI = 0.88 to 2.19). The risk of colon cancer associated with an HFE gene mutation was similar for those who did and did not have a family history of colon cancer. Among those with HFE mutations, cancer risk increased with increasing age and total iron intake. CONCLUSIONS: HFE gene mutations are associated with an increased risk of colon cancer. Cancer risk is greatest in mutation carriers who are older or consume high quantities of iron.     

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

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.     

Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer.

Individuals with the major hemochromatosis (HFE) allele C282Y and iron overload develop hepatocellular and some extrahepatic malignancies at increased rates. No association has been previously reported between the C282Y allele and breast cancer. We hypothesized that due to the pro-oxidant properties of iron, altered iron metabolism in C282Y carriers may promote breast carcinogenesis. Because 1 in 10 Caucasians of Northern European ancestry carries this allele, any impact it may have on breast cancer burden is potentially great. We determined C282Y genotypes in 168 patients who underwent high-dose chemotherapy and blood cell transplantation for cancer: 41 with breast cancer and 127 with predominantly hematological cancers (transplant cohort). Demographic, clinical, and tumor characteristics were reviewed in breast cancer patients. The frequency of C282Y genotypes in breast cancers was compared with the frequency in nonbreast cancers, an outpatient sample from Tennessee (n = 169), and a published United States national sample. The frequency of at least one C282Y allele in breast cancers was higher (36.6%, 5 homozygotes/10 heterozygotes) than frequencies in Tennessee (12.7%, P < 0.001), the general population (12.4%, P < 0.001), and similarly selected nonbreast cancers (17.0%, P = 0.008). The likelihood of breast cancer in the transplant cohort increased with C282Y allele dose (P(trend) = 0.010). These results were supported by the finding in a nontransplant cohort of a higher frequency of C282Y mutations in Caucasian (18.4%, P = 0.039) and African-American (8.5%, P = 0.005) women with breast cancer than race-specific national frequency estimates. A high prevalence of C282Y alleles in women with breast cancer with and without poor risk features suggests that altered iron metabolism in C282Y carriers may promote the development of breast cancer and/or more aggressive forms of the disease.     

Do cancer cells selectively mutate HFE to increase their intracellular iron?

Malignant cells compared to their normal counter-parts, have an increased requirement for iron in order to achieve an enhanced cell growth. Transferrin receptor (TfR), an essential transport protein that enables cells to satisfy their need of iron, is upregulated in cancer cells. The hemochromatosis gene (HFE) produces a protein that interacts with TfR; and we hypothesized that tumor cells would selectively mutate HFE to improve their iron-uptake and thus provide themselves a growth advantage over non-tumor cells. A total of 36 non-small cell lung cancer (NSCLC) samples and matched tumor-free tissue from the same individuals were examined for HFE mutations using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Sequencing analysis of the shifted bands in three of 36 cases (in both, the tumor and matching normal tissue of the same individuals) revealed the cysteine to tyrosine substitution at amino acid residue 282 (C282Y) in the protein. Surprisingly, matching samples from one patient with a heterozygous C282Y mutation in the germline, showed loss of heterozygosity in the tumor sample at the mutant HFE allele resulting in loss of the C282Y and retention of the normal allele. In addition, we examined 45 tumor cell lines from 11 different tissues. Five cell lines had a heterozygous mutation of HFE, none had a homozygous HFE mutation in the coding region. In summary, our experiments suggest that HFE mutations are not associated with a growth advantage for cancer cells.     

Hemochromatosis gene mutations and distal adenomatous colorectal polyps.

Iron has been suggested to be a risk factor for colorectal neoplasia. Some individuals who are heterozygous for mutations in the hemochromatosis gene (HFE) have higher than average serologic measures of iron. We therefore investigated whether heterozygosity for HFE mutations was related to risk of advanced distal adenoma and whether the relationship was affected by dietary iron intake. In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 679 persons with advanced distal adenoma and 697 control persons were genotyped for the two major HFE mutations (C282Y and H63D), one HFE polymorphism (IVS2+4), and one polymorphism (G142S) in the transferrin receptor gene (TFRC). HFE haplotypes were also created to examine the effect of haplotype on risk. Food frequency questionnaire data were used to estimate daily iron intake. There was no relationship between any HFE genotype or haplotype and advanced adenoma. Stratification of HFE genotype by TFRC genotype did not change the results. In addition, there was no relationship between dietary iron intake and risk of adenoma or between HFE genotype and risk of adenoma, stratified by iron intake. These results do not support a relationship between HFE heterozygosity and risk of advanced distal adenoma.     

Significance of Hereditary Hemochromatosis Gene (HFE) Mutations in Chronic Hepatitis C and Hepatocellular Carcinoma Patients in Egypt: A Pilot Study

Background: Hereditary hemochromatosis is a genetic disease defined by enhanced overloading of iron and associated with Chronic Hepatitis C (CHC). This study aims to evaluate the correlation of the HFE gene mutations on Egyptian CHC with liver disease progression and the risk of HCC development. Methods: The HFE mutations (C282Y and H63D) were genotyped on 100 CHC patients and 50 healthy individuals by a hybridization assay. The serum iron content was also measured for all subjects. Results: A significant elevation of the serum iron, ferritin, and TIBC in HCV-infected patients (p≤0.05). The H63D mutation was detected in 23% of the all studied samples. The serum iron and the H63D heterozygosity were correlated significantly between non-cirrhotic and cirrhotic without HCC patients. Conclusion: The H63D heterozygosity might have a potential role in iron accumulation. Moreover, HFE mutations did not tend to be associated with an increased risk of HCC in cirrhotic patients.     

Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis

Background

Hereditary hemochromatosis (HH) is an autosomal recessive disorder mainly associated with homozygosity for the C282Y and H63D mutations in the hemochromatosis (HFE) gene. The reports about the C282Y and H63D mutations and hepatocellular carninoma (HCC) were controversial. To clarify the relationship between C282Y and H63D mutations and HCC, a meta-analysis including nine studies (1102 HCC cases and 3766 controls, mainly came from European populations) was performed.

Methods

The association was measured using random-effect (RE) or fixed-effect (FE) odds ratios (ORs) combined with 95% confidence intervals (CIs) according to the studies'' heterogeneity.

Results

Meta-analysis of nine studies showed that Y allele of C282Y was associated with HCC risk: RE OR reached 1.50 (95%CI: 1.05-2.14, p for heterogeneity = 0.02, I² = 0.57). Subgroup analysis of seven studies also showed Y allele was associated with HCC risk in healthy populations: RE OR reached 1.61 (95%CI: 1.08-2.39, p for heterogeneity = 0.04, I² = 0.55). We further did subgroup analysis in alcoholic liver cirrhosis (LC) patients of four studies (224 cases and 380 controls) and found that both the dominant model and Y allele of C282Y were associated with HCC risk (FE OR reached 4.06, 95%CI: 2.08-7.92 and 3.41, 95%CI: 1.81-6.41, respectively). There was no distinct heterogeneity among the studies (I² = 0). Sensitivity analyses showed the results were robust in the subgroup analysis of alcoholic LC patients.

Conclusions

C282Y mutation was associated with HCC in European alcoholic LC patients.     

Interaction between haemochromatosis and transferrin receptor genes in hepatocellular carcinoma

In hepatocellular carcinoma (HCC) iron has been implicated as a risk factor primarily in patients with hereditary haemochromatosis (HH) and cirrhosis. The wild-type HH (HFE) protein complexes with the transferrin receptor (TFR), and two HFE mutations (Cys282Tyr and His63Asp) have been found to increase the affinity of the TFR for transferrin resulting in an increased cellular uptake of iron. In previous studies we found an interaction between HFE and TFR genotypes in multiple myeloma and breast and colorectal carcinomas. In the present investigation we have studied HFE and TFR genotypes in 54 Swedish patients with HCC, using DNA from archival samples of paraffin wax blocks. The same HFE-TFR interaction as in the previously studied neoplastic disorders was found. Individuals carrying the HFE282Tyr allele (homo- and heterozygotes) in combination with homozygosity for the TFR Ser allele showed an increased risk for HCC (OR = 3.5; 95% confidence interval, CI = 1.3-9.3), which was further increased in HFE Tyr homozygotes and compound (Tyr/Asp) heterozygotes in combination with TFR 142Ser homozygosity (OR = 17.2; 95% CI = 1.8-168.9). The presence of liver cirrhosis could only be assessed in part of the patient material. In patients with verified liver cirrhosis the risk figures were substantially increased: for HFE 282 Tyr carriers in combination with TFR 142 Ser/Ser OR = 7.2; 95% CI = 2.0-25.5 and for HFE 282Tyr homozygotes and compound heterozygotes in combination with TFR 142Ser homozygosity, OR = 62.8; 95% CI = 6.1-642.5.     

Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer.

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.     

HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A

HFE is a protein that impacts cellular iron uptake. HFE gene variants are identified as risk factors or modifiers for multiple diseases. Using HFE stably transfected human neuroblastoma cells, we found that cells carrying the C282Y HFE variant do not differentiate when exposed to retinoic acid. Therefore, we hypothesized HFE variants would impact response to therapeutic agents. Both the human neuroblastoma and glioma cells that express the C282Y HFE variant are resistant to Temodar, geldanamycin and γ-radiation. A gene array analysis revealed that p16INK4A (p16) expression was increased in association with C282Y expression. Decreasing p16 protein by siRNA resulted in increased vulnerability to all of the therapeutic agents suggesting that p16 is responsible for the resistance. Decreasing HFE expression by siRNA resulted in a 85% decrease in p16 expression in the neuroblastoma cells but not the astrocytoma cells. These data suggest a potential direct relationship between HFE and p16 that may be cell specific or mediated by different pathways in the different cell types. In conclusion, the C282Y HFE variant impacts the vulnerability of cancer cells to current treatment strategies apparently by increasing expression of p16. Although best known as a tumor suppressor, there are multiple reports that p16 is elevated in some forms of cancer. Given the frequency of the HFE gene variants, as high as 10% of the Caucasian population, these data provide compelling evidence that the C282Y HFE variant should be part of a pharmacogenetic strategy for evaluating treatment efficacy in cancer cells.     

Interaction between haemochromatosis and transferrin receptor genes in different neoplastic disorders.

A number of genes are involved in iron metabolism, including the transferrin receptor (TFR) and haemochromatosis (HFE) genes. In previous investigations an increased risk for neoplastic disease has been observed in individuals homo- and heterozygous for hereditary haemochromatosis. The HFE wild-type gene product complexes with the transferrin receptor (TF) and two different HFE mutations (Cys282Tyr and His63Asp) have been found to increase the affinity of TFR for TF and increase cellular iron uptake. In a recent study we found no associations for HFE and TFR separately, but an interaction between HFE and TFR genotypes in multiple myeloma. Individuals carrying the HFE Tyr282 allele (homo- and heterozygotes) in combination with homozygosity for the TFR Ser142 allele had an increased risk. In the present study the same association was found in breast and colorectal cancer. The odds ratio for all three neoplasms combined was 2.0 (95% CI 1.0-3.8). The risk for neoplastic disease was further increased (OR 7.7, 95% CI = 1.0-59.9) when the analysis was restricted to HFE Tyr homozygotes and compound heterozygotes in combination with TFR Ser homozygosity. Thus, an interaction between HFE and TFR alleles may increase the risk for different neoplastic disorders.     

Meta-Analysis of the Association between H63D and C282Y Polymorphisms in HFE and Cancer Risk

Background: Previous studies suggested that the H63D and C282Y polymorphisms in the HFE genes weresusceptible to many cancer types, nevertheless, the present results were inconclusive. Thus, the present studywas aimed to evaluate the association between the HFE polymorphisms (H63D and C282Y) and cancer riskvia meta-analysis. Materials and Methods: We retrieved PubMed, Google Scholar, Embase and Web of Sciencedatabases for all eligible studies up to April 1, 2015. All the statistical analysis was conducted by STATA 12.0.Results: Finally, a total of 20 publications including 24 case-control studies, comprising 6,524 cases and 31,080controls for HFE-C282Y polymorphism and 19 publications including 21 case control studies, comprising 5,648cases and 14,257 controls for HFE-H63D polymorphism were enrolled in our analysis. An increased risk for overallcancer risk was identified in HFE-H63D polymorphism under allele contrast (D vs H: OR=1.153; 95%CI=1.031-1.289, Pheterogeneity=0.002), homozygotes vs wide type (DD vs HH: OR=1.449; 95%CI=1.182-1.777,Pheterogeneity=0.391), dominant model (DD+HD vs HH: OR=1.145; 95%CI=1.007-1.301, Pheterogeneity=0.002)and recessive model (DD vs HD+HH: OR=1.416 ; 95%CI=1.156-1.735, Pheterogeneity=0.549), as well as HFEC282Yunder homozygotes vs wide type (YY vs CC: OR=1.428, 95%CI=1.017-2.006, Pheterogeneity=0.220). Inaddition, in the stratified analysis by cancer type, an increased risk was identified in hepatocellular carcinomaand breast cancer in C282Y polymorphism, as well as pancreatic cancer in H63D polymorphism, whereas adecreased risk of colorectal cancer was identified in C282Y polymorphism. Conclusions: Present study suggestedthat H63D and C282Y polymorphisms associated with an increased risk of overall cancer. Nevertheless, welldesignedstudy with large sample size will be continued on this issue of interest.     

HFE H63D mutation frequency shows an increase in Turkish women with breast cancer

Background  

The hereditary hemochromatosis gene HFE plays a pivotal role in iron homeostasis. The association between cancer and HFE hetero- or homozygosity has previously been shown including hepatocellular and nonhepatocellular malignancies. This study was performed to compare frequencies of HFE C282Y and H63D variants in Turkish women with breast cancer and healthy controls.     

Carriage of HFE mutations and outcome of surgical resection for hepatocellular carcinoma in cirrhotic patients

BACKGROUND: Aggressive hepatocellular carcinoma (HCC) complicates frequently hereditary hemochromatosis, a disease for which a strong candidate gene, named HFE, has recently been identified. Patients with HCC who are heterozygotes for mutations in the HFE gene might have distinct features and a distinct disease course. METHODS: The presence of the 2 mutations associated with hereditary hemochromatosis (C282Y and H63D) was sought by restriction fragment length polymorphism in 61 cirrhotic patients (46 males and 15 females) who underwent resection for HCC at a single institution. RESULTS: There were 4 heterozygotes for the C282Y mutation and 6 homozygotes + 20 heterozygotes for the H63D mutation, with no compound heterozygotes. Carriage of >/= 1 HFE mutated allele was significantly more frequent in HCC patients than in 149 control subjects (44% vs. 29%, P = 0.005). Among C282Y heterozygotes, 3 of 4 were female, compared with 12 of 57 wild-type carriers (P = 0.015); no gender distribution existed among patients carrying H63D alleles (6 of 26 vs. 9 of 35, P = 0.813). Survival was longer for patients with wild-type HFE than for those with mutated HFE (67% vs. 22% at 3 years; hazard ratio = 0.42, 95% confidence interval = 0.21-0.80) (P < 0.01). The negative effect on survival that resulted from possessing >/= 1 HFE mutated allele was maintained even after adjustment for gender, age, presence of tumor capsule, presence of comorbid factors, Okuda stage, Edmonson grading, and number of lesions (P = 0.01). CONCLUSIONS: Testing for HFE mutations may help identify HCC patients with dismal prognoses for whom surgical resection may not represent the best treatment option.     

Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer.

Iron overload has been noticed as a feature of human breast cancer. Cellular iron uptake is regulated by the hemochromatosis and transferrin receptor system, mutations of which cause the iron storage disease hereditary hemochromatosis. To understand the role of hemochromatosis and transferrin receptor system mutations in breast cancer, we analyzed 19 sequence variations at HFE, TFR1, TFR2, and FPN1 and compared genotype frequencies between cases and controls in a German population. There were 688 breast cancer patients and 724 population-based and age-matched controls. For genotyping, we applied the Hemochromatosis Strip Assay and TaqMan allelic discrimination analyses. In addition to genotype frequencies, we established frequencies of compound genotypes. The frequencies of HFE at His63Asp, Ser65Cys, and Cys282Tyr, and of TFR1 at Ser142Gly minor alleles in this German population were 15.9%, 1.8%, 5.6%, and 46.0%, respectively. No rare variants at 15 more loci at HFE, TFR2, and FPN1 were observed in breast cancer patients. There were no significant differences of allele and genotype frequencies between cases and controls. Triple and quadruple compound genotypes at HFE_His63_Cys282-TFR1_Ser142Gly and HFE_His63_Ser65_Cys282-TFR1_Ser142Gly showed a nonsignificant increase in cases. Although limited by low numbers, an increased prevalence of the HFE Tyr282 minor allele was observed in breast cancer cases with a high number of affected lymph nodes (P = 0.032). Our data suggest that variants of the hemochromatosis-transferrin receptor system have no direct effect on the incidence of breast cancer in Germany. Possible effects on tumor progression and prognosis remain elusive.     

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

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI = 0.83–2.35), which increased to 2.96 (95% CI = 1.29–6.80) in the presence of a particular TFRC genotype for rs3817672 (Pinteraction = 0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR = 2.54, 95% CI = 1.05–6.12; Pinteraction with ethnicity = 0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR = 1.52–2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR = 2.0 per incremental change, 95% CI = 1.29–3.12; P = 0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.     

In vitro drug resistance to imatinib and mutation of ABL gene in childhood Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia

Imatinib, the ABL kinase inhibitor, is used not only for Philadelphia chromosome-positive (Ph + ) chronic myelogenous leukemia, but also for Ph + acute lymphoblastic leukemia (ALL), although resistance to the drug tends to develop in an early stage of the clinical course. We describe a childhood refractory Ph + ALL patient in whom progressive resistance to imatinib was correlated with the appearance of a mutation in the BCR-ABL kinase domain and in vitro drug resistance to imatinib as determined by the methyl-thiazol-tetrazolium (MTT) assay. A missense mutation of T to C (Y253H) of the ABL gene was identified in the resistant clone, suggesting that this mutation may play an etiological role in the rapid loss of drug sensitivity.     

Associations between AT-rich Interactive Domain 5B gene Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia: a Meta-analysis

Previous genome-wide association studies (GWAS) have implicated several single nucleotide polymorphisms (SNPs) in the AT-rich interactive domain 5B (ARID5B) gene with childhood acute lymphoblastic leukemia (ALL). However, replicated studies reported some inconsistent results in different populations. Using meta-analysis, we here aimed to clarify the nature of the genetic risks contributed by the two polymorphisms (rs10994982, rs7089424) for developing childhood ALL. Through searches of PubMed, EMBASE, and manually searchingrelevant references, a total of 14 articles with 16 independent studies were included. Odds ratios (ORs) with 95% confidence intervals (95%CI) were calculated to assess the associations. Both SNPs rs10994982 and rs7089424showed significant associations with childhood ALL risk in all genetic models after Bonferroni correction. Furthermore, subtype analyses of B-lineage ALL provided strong evidence that SNP rs10994982 is highly associated with the risk of developing B-hyperdiploid ALL. These results indicate that SNPs rs10994982 andrs7089424 are indeed significantly associated with increased risk of childhood ALL.