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Malignant melanoma is one of the most highly ranked cancers in terms of years of life lost. Hereditary melanoma with its increased familial susceptibility is thought to affect up to 12% of all melanoma patients. In the past, only a few high-penetrance genes associated with familial melanoma, such as CDKN2A and CDK4 , have been clinically tested. However, findings now indicate that melanoma is a cancer most likely to develop not only due to high-penetrance variants but also due to polygenic inheritance patterns, leaving no clear division between the hereditary and sporadic development of malignant melanoma. Various pathogenic low-penetrance variants were recently discovered through genome-wide association studies, and are now translated into polygenic risk scores. These can show superior sensitivity rates for the prediction of melanoma susceptibility and related mixed cancer syndromes than risk scores based on phenotypic traits of the patients, with odds ratios of up to 5.7 for patients in risk groups. In addition to describing genetic findings, we also review the first results of epigenetic research showing constitutional methylation changes that alter the susceptibility to cutaneous melanoma and its risk factors., Competing Interests: None., (IJMEG Copyright © 2021.)

Purpose: Several lines of evidence indicate that the Hippo/Yes-associated protein 1 (YAP1) pathways might play a role in the pathogenesis of asthma. To investigate the possible role of the Hippo/YAP1 pathway in the pathogenesis of asthma or its phenotypes., Methods: The levels of gene expressions of the members of the Hippo/YAP1 were compared. The presence of the proteins of the YAP1 and FRMD6 were analyzed with Western blot in induced sputum of 18 asthmatic subjects and 10 control subjects. Fourteen single nucleotide polymorphisms (SNPs) in the YAP1 gene were genotyped in 522 asthmatic subjects and 711 healthy controls. The results were evaluated with traditional frequentist methods and with Bayesian network-based Bayesian multilevel analysis of relevance (BN-BMLA)., Results: The mRNA of all the members of the Hippo/YAP1 pathway could be detected in the induced sputum of both controls and cases. A correlation was found between YAP1 mRNA levels and sputum bronchial epithelial cells (r=0.575, P=0.003). The signal for the FRMD6 protein could be detected in all sputum samples while the YAP1 protein could not be detected in the sputum samples, of the healthy controls and severe asthmatics, but it was detectable in mild asthmatics. The rs2846836 SNP of the YAP1 gene was significantly associated with exercise-induced asthma (odds ratio [OR]=2.1 [1.3-3.4]; P=0.004). The distribution of genotypes of rs11225138 and certain haplotypes of the YAP1 gene showed significant differences between different asthma severity statuses. With BN-BMLA, 2 SNPs, genetic variations in the FRMD6 gene proved to be the most relevant to exercise-induced asthma and allergic rhinitis. These 2 SNPs through allergic rhinitis and exercise-induced asthma were in epistatic interaction with each other., Conclusions: Our results provided additional evidence that the FRMD6/Hippo/YAP1 pathway plays a role in the pathogenesis of asthma. If additional studies can confirm these findings, this pathway can be a potential novel therapeutic target in asthma and other inflammatory airway diseases., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2017 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease)

Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1, ABCC2, ABCC3, ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.

Background: Cytarabine (cytosine arabinoside, ara-C) is a chemotherapeutical agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). Adverse drug reactions, such as interpatient variability in sensitivity to ara-C, are considerable and may cause difficulties during chemotherapy. Single nucleotide polymorphisms (SNPs) can play a significant role in modifying nucleoside-drug pharmacokinetics and pharmacodynamics and thus the development of adverse effects. Our aim was to determine whether polymorphisms in genes encoding transporters and enzymes responsible for the metabolism of ara-C are associated with toxicity and clinical outcome in a patient population with childhood ALL., Procedure: We studied 8 SNPs in the CDA, DCK, DCTD, SLC28A3, and SLC29A1 genes in 144 patients with childhood acute lymphoblastic leukemia treated according to ALLIC BFM 1990, 1995 and 2002 protocols., Results: DCK rs12648166 and DCK rs4694362 SNPs were associated with hematologic toxicity (OR = 2.63, CI 95% = 1.37-5.04, P = 0.0036 and OR = 2.53, CI 95% = 1.34-4.80, P = 0.0044, respectively)., Conclusions: Our results indicate that DCK polymorphisms might be important genetic risk factors for hematologic toxicity during ALL treatment with ara-C. Individualized chemotherapy based on genetic profiling may help to optimize ara-C dosing, leading to improvements in clinical outcome and reduced toxicity., (© 2015 Wiley Periodicals, Inc.)

High-dose methotrexate (HD-MTX) plays an important role in the consolidation therapy of acute lymphoblastic leukaemia (ALL) in many treatment regimens worldwide. However, there is a large interpatient variability in the pharmacokinetics and toxicity of the drug. We investigated the influence of single nucleotide polymorphisms (SNPs) in genes of the folate metabolic pathway, transporter molecules and transcription proteins on the pharmacokinetics and toxicity of MTX and 7-hydroxy-methotrexate (7-OH-MTX). 63 SNPs of 14 genes were genotyped and a total of 463 HD-MTX courses (administered according to the ALL-BFM 95 and ALL IC-BFM 2002 protocols) were analysed. Haematological, hepatic and renal toxicities, estimated by routine laboratory parameters were evaluated. Random forest and regression trees were used for variable selection and model building. Linear mixed models were established to prove the significance of the selected variables. SNPs (rs4948502, rs4948496, rs4948487) of the ARID5B gene were associated with the serum levels of MTX (P < 0·02), serum levels and area under the curve of 7-OH-MTX (P < 0·02) and with hypoproteinaemia (P = 0·004). SLCO1B1 rs4149056 also showed a significant association with serum MTX levels (P < 0·001). Our findings confirm the association of novel genetic variations in folate-related and ARID5B genes with the serum MTX levels and acute toxicity., (© 2014 John Wiley & Sons Ltd.)

Background: Galectins are potent immune regulators, with galectin-8 acting as a pro-apoptotic effector on synovial fluid cells and thymocytes and stimulator on T-cells. To set a proof-of-principle example for risk assessment in autoimmunity, and for a mutation affecting physiological galectin sensor functions, a polymorphism in the coding region of the galectin-8 gene (rs2737713; F19Y) was studied for its association with two autoimmune disorders, i.e. rheumatoid arthritis and myasthenia gravis., Methods: A case-control analysis and a related quantitative trait-association study were performed to investigate the association of this polymorphism in patients (myasthenia gravis 149, rheumatoid arthritis 214 and 134 as primary and repetitive cohorts, respectively) and 365 ethnically matched (Caucasian) healthy controls. Distribution was also investigated in patients grouped according to their antibody status and age at disease onset. Comparative testing for lectin activity was carried out in ELISA/ELLA-based binding tests with both wild-type and F19Y mutant galectin-8 from peripheral blood mononuclear cell lysates of healthy individuals with different genotypes as well as with recombinant wild-type and F19Y mutant galectin-8 proteins., Results: A strong association was found for rheumatoid arthritis, and a mild one with myasthenia gravis. Furthermore, the presence of the sequence deviation also correlated with age at disease onset in the case of rheumatoid arthritis. The F19Y substitution did not appear to affect carbohydrate binding in solid-phase assays markedly., General Significance: This is the first report of an association between a galectin-based polymorphism leading to a mutant protein and autoimmune diseases, with evidence for antagonistic pleiotropy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: We carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population., Methods: The results were evaluated with traditional statistical methods and with our newly developed Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method. We collected genomic DNA and clinical data from 543 children, who underwent chemotherapy due to ALL, and 529 healthy controls. Altogether 66 single nucleotide polymorphisms (SNPs) in 19 candidate genes were genotyped., Results: With logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL. Because the associated SNPs were in linkage in each gene, these associations corresponded to one signal per gene. The odds ratio (OR) associated with the tag SNPs were: OR = 1.69, P = 2.22x10(-7) for rs4132601 (IKZF1), OR = 1.53, P = 1.95x10(-5) for rs10821936 (ARID5B) and OR = 0.64, P = 2.32x10(-4) for rs12949918 (STAT3). With the BN-BMLA we confirmed the findings of the frequentist-based method and received additional information about the nature of the relations between the SNPs and the disease. E.g. the rs10821936 in ARID5B and rs17405722 in STAT3 showed a weak interaction, and in case of T-cell lineage sample group, the gender showed a weak interaction with three SNPs in three genes. In the hyperdiploid patient group the BN-BMLA detected a strong interaction among SNPs in the NOTCH1, STAT1, STAT3 and BCL2 genes. Evaluating the survival rate of the patients with ALL, the BN-BMLA showed that besides risk groups and subtypes, genetic variations in the BAX and CEBPA genes might also influence the probability of survival of the patients., Conclusions: In the present study we confirmed the roles of genetic variations in ARID5B and IKZF1 in the susceptibility to B-cell ALL. With the newly developed BN-BMLA method several gene-gene, gene-phenotype and phenotype-phenotype connections were revealed. We showed several advantageous features of the new method, and suggested that in gene association studies the BN-BMLA might be a useful supplementary to the traditional frequentist-based statistical method.

In the last few years, it has been recognized that the unbalanced regulation of survival and apoptosis of bronchial inflammatory cells is a key component in the development of asthma. Baculoviral IAP repeat containing 5 (BIRC5) (also known as survivin) is an important anti-apoptotic protein that has been implicated in many cancer types, and recent studies provide evidence for its role in controlling inflammatory disorders as well. Our aim was to investigate at both genetic and transcriptional levels if BIRC5 has an impact on asthma development. We found that induced sputum samples of patients with bronchial asthma contained elevated levels of BIRC5 mRNA compared with healthy subjects and its level was in correlation with sputum eosinophil percentages. Furthermore, in a case-control study examining single nucleotide polymorphisms (SNPs) in the BIRC5 regulatory regions, the minor alleles of rs8073903 and rs8073069 were found to be significantly associated with asthma and especially non-allergic asthma phenotypes, which associations were more prominent among women. Two marker haplotype analyses further strengthen the impact of these two polymorphisms on both asthma and non-allergic asthma. In the female cohort, rs1508147 was also significantly associated with increased risk of non-allergic asthma. Additionally, with linear regression analysis, we showed that rs9904341 was significantly correlated with both absolute and relative serum eosinophil levels. In conclusion, our results suggest that possibly by inhibition of the eosinophil apoptosis, BIRC5 might be an important regulator of the asthmatic processes and we provide some evidence that its effect might be affected by SNPs located in the gene regulatory regions.

Air pollution and subsequent increased oxidative stress have long been recognized as contributing factors for asthma phenotypes. Individual susceptibility to oxidative stress is determined by genetic variations of the antioxidant defence system. In this study, we analysed the association between environmental nitrogen dioxide (NO(2)) exposure and single nucleotide polymorphisms (SNP) in NFE2L2 and KEAP1 genes and their common impact on asthma risk. We genotyped 12 SNPs in a case-control study of 307 patients diagnosed with asthma and 344 controls. NO(2) concentration was collected from the period preceding the development of asthma symptoms. Multiple logistic regression was applied to evaluate the effects of the studied genetic variations on asthma outcomes in interaction with NO(2) exposure. Our data showed that genotypes of rs2588882 and rs6721961 in the regulatory regions of the NFE2L2 gene were inversely associated with infection-induced asthma (odds ratio (OR) = 0.290, p = 0.0015, and OR = 0.437, p = 0.007, respectively). Furthermore, case-only analyses revealed significant differences for these SNPs between asthma patients that lived in modestly or highly polluted environment (OR = 0.43 (0.23-0.82), p = 0.01, and OR = 0.51, p = 0.02, respectively, in a dominant model). In conclusion, our results throw some new light upon the impact of NFE2L2 polymorphisms on infection-induced asthma risk and their effect in gene-environment interactions.

Anthracyclines are potent cytostatic drugs, the correct dosage being critical to avoid possible cardiac side effects. ABCC1 [ATP-binding cassette, sub-family C, member 1; also denoted as MRP1 (multidrug resistance-associated protein 1)] is expressed in the heart and takes part in the detoxification and protection of cells from the toxic effects of xenobiotics, including anthracyclines. Our objective was to search for associations between LV (left ventricular) function and single-nucleotide polymorphisms of the ABCC1 gene in children receiving anthracycline chemotherapy. Data of 235 paediatric patients with acute lymphoblastic leukaemia was analysed. Patients were followed-up by echocardiography (median follow-up 6.3 years). Nine polymorphisms in the ABCC1 gene were genotyped. The ABCC1 rs3743527TT genotype and rs3743527TT–rs246221TC/TT genotype combination were associated with lower LVFS (left ventricular fractional shortening) after chemotherapy. The results suggest that genetic variants in the ABCC1 gene influence anthracycline-induced LV dysfunction., (© The Author(s) Journal compilation © 2012 Portland Press Limited)

Background: Histamine as an inflammatory mediator plays an important role in chronic allergic and asthmatic conditions. However, the role of genetic polymorphisms of the histamine receptor HRH4 (histamine receptor H4) gene in asthma susceptibility and endophenotypes has not been studied yet. Our aim was to investigate the possible association between single nucleotide polymorphisms (SNPs) in the HRH4 gene and asthma or some endophenotypes of asthma., Methods: Twenty-one SNPs of the HRH4 gene were genotyped in 313 asthmatic patients and 360 controls using Sequenom® iPLEX® Gold Genotyping Technology., Results: Genotype distribution of three HRH4 SNPs, namely rs17187619 [p = 0.002; odds ratio, OR (95% confidence interval, CI) = 2.4 (4.1-1.4)], rs527790 [p = 0.0002; OR (95% CI) = 3.3 (6.1-1.8)] and rs487202 [p = 0.00007; OR (95% CI) = 3.5 (6.6-1.9)] differed significantly between patients with or without infection-induced asthma. Haplotypes, which included the rs4800573-rs527790 CC allele combination, were found to be associated with infection-induced asthma [p = 0.0009, OR (95% CI) = 0.5 (0.4-0.8)]. The rs487202-rs574913 CA haplotype was more frequent among patients with infection-induced asthma [p = 0.0006, OR (95% CI) = 1.9 (1.3-2.6)]. None of the SNPs contributed directly to the risk of asthma., Conclusions: Our results suggest that genetic variation in the HRH4 gene might influence the pathogenesis of infection-induced asthma., (Copyright © 2012 S. Karger AG, Basel.)

Background: The objective of this report was to estimate long-term outcome and prognostic factors in children and adolescents with osteosarcoma. A large group of osteosarcoma patients were analyzed at our national oncology center., Procedure: To evaluate the efficacy of surgery and multiagent chemotherapy for treating osteosarcoma, we reviewed 122 cases (65 male, 57 female, mean age 13.8 ± 3.6 years) treated at the Second Department of Pediatrics in Budapest between 1988 and 2006. Demographic parameters, tumor-related and treatment-related variables, response, overall survival (OS) and event-free survival (EFS) were analyzed., Results: The 5-year OS was 68% and 5-year EFS was 62%. OS of patients without metastasis was 79%, while OS with early metastasis was 17%. Survival of patients with amputation (n = 30) was not significantly different from patients with limb-salvage surgery (n = 82), but all patients without radical surgery died. Gender and histological classification had no prognostic significance. Patients with localized tumors in extremities had increased survival compared to patients with axial skeleton tumors (P = 0.013). Poor histological response to neoadjuvant chemotherapy (rate of survivor tumor cells >10%) was associated with decreased survival (P = 0.018). Patients under 14 years had better EFS than patients over 14 years (P = 0.008)., Conclusions: Our results demonstrate that younger patients with localized osteosarcoma of the extremities who receive limb-salvage surgery and chemotherapy have an excellent survival., (Copyright © 2011 Wiley-Liss, Inc.)

CHI3L1 gene encodes for a glycoprotein (HC-gp39 or YKL40) secreted by synovial fibroblasts, macrophages, neutrophil granulocytes and chondrocytes. Its expression is under the control of NF-kB. It is regarded as an acute phase protein, and its levels are significantly elevated in rheumatic diseases. Furthermore, HC-gp39 has been shown to be recognized by autoreactive T cells in rheumatoid arthritis. In the present study, we have examined two functional variants of the promoter region of CHI3L1 gene (CHI3L1-1 (rs4950928) and CHI3L1-2 (rs10399931) that have been reported earlier to be associated with schizophrenia and sarcoidosis. We used TaqMan allelic discrimination assays to study the genotypes of Hungarian patients with rheumatoid arthritis (n = 182) and of healthy controls (n = 194). No significant association of the investigated SNPs with the disease was found. Here we report that CHI3L1 SNPs, shown to be involved in the predisposition of schizophrenia, are not associated with rheumatoid arthritis.

Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium.

Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage.

In this study, we aimed to identify novel genes involved in experimental and human asthma, importance of which has not yet been recognized. In an ovalbumin-induced murine model of asthma, we applied microarray gene expression analysis at different time points after allergen challenges. Advanced statistical methods were used to relate gene expression changes to cellular processes and to integrate our results into multiple levels of information available in public databases. At 4 h after the first allergen challenge, gene expression pattern reflected mainly an acute, but non-atopic, inflammatory response and strong chemotactic activity. At 24 h after the third allergen challenge, gene set enrichment analysis revealed significant over-representation of gene sets corresponding to T(h)2-type inflammation models. Among the top down-regulated transcripts, an anti-oxidant enzyme, paraoxonase-1 (PON1), was identified. In human asthmatic patients, we found that serum PON1 activity was reduced at exacerbation, but increased parallel with improving asthma symptoms. PON1 gene polymorphisms did not influence the susceptibility to the disease. Our observations suggest that an altered PON1 activity might be involved in the pathogenesis of asthma, and serum PON1 level might be used for following up the effect of therapy.

To investigate their possible roles in disease susceptibility and some disease characteristics we genotyped C3435T and G2677T/A polymorphisms in multidrug resistance-1 (MDR1) gene with a single base extension method and the G34A and C421A polymorphisms of the breast cancer resistance protein gene with an allelic discrimination system in 396 children with acute lymphoblastic leukaemia (ALL) and 192 control patients. While the distribution of individual alleles and genotypes did not differ between patients and controls, there were significant differences in the frequencies of some rare haplotypes and genotype combinations in the MDR1 gene between the two groups.

We examined the association of functional ABCB1 (MDR1) and ABCG2 (BCRP) polymorphisms with acute side effects of chemotherapy. Analyses were performed on clinical data from 138 patients treated with the ALL-BFM-95 protocol implying several substrates of these transporters. ABCB1 3435T>C, 2677G>T/A 1236C>T and ABCG2 421C>A genotypes were determined. A higher proportion of ABCB1 3435TT patients suffered excessive infectious complications than those harbouring at least one C allele (OR=2.5, p=0.03) during the whole half-year-long intensive phase of chemotherapy. Weaker associations were calculated when ABCB1 1236T-2677T-3435T haplotype homozygotes were tested against the remaining part of the population (OR=2.3, p=0.09). During the reinduction phase of therapy, the occurrence of severe leukocytopenia was similar among ABCB1 genotype groups. The frequency of any toxicities were not shown to differ according to the ABCG2 421C>A genotype. Our data suggest that the ABCB1 3435T>C genotype is associated with the infectious complications of the applied chemotherapy regimen.