A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia

Methotrexate (MTX) is an important component of therapy used to treat childhood acute lymphoblastic leukemia (ALL). Two single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, affect MTHFR activity. A large body of studies has investigated the potential role of MTHFR SNPs in MTX toxicity in pediatric ALL. However, the results are controversial. In this review and meta-analysis, we critically evaluate the relationship between the C677T and A1298C polymorphisms of MTHFR and MTX toxicity in pediatric ALL. The majority of published reports do not find associations between MTHFR polymorphisms and toxicity in pediatric ALL. When associations are reported, often the results are contradictory to each other. The meta-analysis confirms a lack of association. In conclusion, MTHFR, C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity in pediatric ALL.This project was supported by RTICC (RD/06/0020/0048), Basque Government (GIC10/71, SAI10/03), and UPV/EHU (UFI11/35). ELL was supported by a predoctoral grant from the Basque Government

Circulating MiRNAs As Biomarkers In Diffuse Large B-Cell lymphoma: A Systematic Review

This study was funded by the Basque Government (IT989-16), and UPV/EHU (UFI11/35). The funding source did not have any role in study design, collection, analysis and interpretation of data, writing of the report, or decision to submit the article for publication

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

Methotrexate (MTX) is an important component in the therapy used to treat childhood acute lymphoblastic leukemia ( ALL). Methylenetetrahydrofolate reductase ( MTHFR) is a key enzyme for MTX pharmacokinetics. Two single-nucleotide polymorphisms in MTHFR gene, C677T and A1298C, affecting MTHFR activity, have been widely studied as potential markers of MTX toxicity and/or outcome in pediatric ALL. In this review, we show that the majority of published reports do not find association or present opposite effect. Therefore, MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL. The efforts should be focused on other genes, such as transporter genes or microRNA-related genes

Systematic Review of the Potential of MicroRNAs in Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin's lymphoma (NHL). DLBCL presents with variable backgrounds, which results in heterogeneous outcomes among patients. Although new tools have been developed for the classification and management of patients, 40% of them still have primary refractory disease or relapse. In addition, multiple factors regarding the pathogenesis of this disease remain unclear and identification of novel biomarkers is needed. In this context, recent investigations point to microRNAs as useful biomarkers in cancer. The aim of this systematic review was to provide new insight into the role of miRNAs in the diagnosis, classification, treatment response and prognosis of DLBCL patients. We used the following terms in PubMed" (('Non-coding RNA') OR ('microRNA' OR 'miRNA' OR 'miR') OR ('exosome') OR ('extracellular vesicle') OR ('secretome')) AND ('Diffuse large B cell lymphoma' OR 'DLBCL')" to search for studies evaluating miRNAs as a diagnosis, subtype, treatment response or prognosis biomarkers in primary DLBCL in human patient populations. As a result, the analysis was restricted to the role of miRNAs in tumor tissue and we did not consider circulating miRNAs. A total of thirty-six studies met the inclusion criteria. Among them, twenty-one were classified in the diagnosis category, twenty in classification, five in treatment response and nineteen in prognosis. In this review, we have identified miR-155-5p and miR-21-5p as miRNAs of potential utility for diagnosis, while miR-155-5p and miR-221-3p could be useful for classification. Further studies are needed to exploit the potential of this field.This study was funded by the Basque Government (IT989-16), and Bioef-EiTB maratoia (BIO15/CA/022). The funding source did not have any role in the study design, collection, analysis and interpretation of data, writing of the report, or decision to submit the article for publication

Osteosarkoma pediatrikoarekiko suszeptibilitatean inplikatuta dauden aldaera genetikoak

Osteosarcoma (OS) is the most common primary bone cancer that occurs primarily in children, adolescents, and young adults. The fact that OS occurs at an early age suggests that there is a strong genetic component at its source. Several studies have suggested that susceptibility to OS development is due to small common low-pene trance variants, such as SNPs. The implication of the common genetic variants in the susceptibility to cancer has already been demonstrated in several studies. One of the most non-coding RNAs studied in cancer are miRNAs and are known to be involved in the origin and evolution of various cancers. Therefore, we analyzed all the genetic vari-ability of the genes of the miRNAs processing path and their implication in the suscep-tibility of the OS. As a result, we decided to validate the association between the ge-netic variants previously associated with the risk to develop OS and to look for new risk markers in the genes related to the miRNAs. Our results indicated that a SNP in the CTLA4 gene could be a marker of susceptibility to develop OS along with the hotspot in the 14q32 region.; Osteosarkoma (OS) edo sarkoma osteogenikoa gazteen artean gertatzen den hezur-minbizirik ohikoena da. Adin hain goiztiarretan sortzeak adierazten du haren jatorrian genetikak paper garrantzitsua duela. Izan ere, hainbat ikerketa-lanen arabera, sarkortasun txikiko aldaera genetikoak (SNPak, esaterako) OSaren kausa izan ohi dira. Jakina da beste minbizi mota batzuetan aldaera genetikoek gaixotasun horrekiko suszeptibilitatean eragina izaten dutela. miRNAk dira minbizien jatorri eta bilakaeran gehien aztertu diren RNA ez-kodetzaileak (ncRNA). Hori dela eta, bai gune kodetzaileetan bai ez-kodetzaileetan (miRNAk eta hauek prozesatzen dituzten geneak) zen aldakortasun genetikoa aztertu genuen. Lan honetan, OSarekiko suszeptibilitatean eragina duten aldaera genetikoen bilaketa egin genuen. Gure emaitzek CTLA4 genea eta 14q32 guneko miRNA taldeak OSarekiko suszeptibilitatearen hotspot-ak izan daitezkeela erakusten dute

Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia

Background: Methotrexate (MTX) is an important component of the therapy for childhood acute lymphoblastic leukemia. Treatment with high-dose MTX often causes toxicity, recommending a dose reduction and/or cessation of treatment. Polymorphisms in genes involved in the MTX metabolism have been associated with toxicity with controversial results. The discrepancies could be due to differences in treatment protocols among studies, small, or non-homogeneous populations or the use of different toxicity criteria. The aim of the present study was to analyze the possible correlation of polymorphisms of genes involved in the MTX metabolism with the toxicity during therapy with the well-established LAL/SHOP protocol. Procedure: We analyzed 10 polymorphisms in seven genes (MTHFR, TS, SHMT1, RFC1, ABCB1, ABCG2, and SLCO1B1) from the MTX metabolism in 115 Spanish pediatric B-ALL patients, using MTX plasma concentration as an objective and quantifiable marker of toxicity. Results: We confirmed the suitability of MTX plasma levels as a toxicity marker. We found a statistically significant association between MTX plasma concentration and the SLCO1B1 rs11045879 CC genotype (P = 0.030). The rs4149081 AA genotype, in the same gene, could also be an indicator for high-MTX plasma concentrations. We did not find any significant association in the other genetic polymorphisms analyzed. Conclusions: Identification of the rs4149081 and rs11045879 SLCO1B1 polymorphisms in children with ALL could be a useful tool for monitoring patients at risk of low-MTX clearance in order to avoid MTX-related toxicity.ELL was supported by a predoctoral grant from the Basque Government. This project was supported by RTICS(RD/06/0020/0048) and Basque Government (iT-463-07 and 2006111015)

Variants in the 14q32 miRNA cluster are associated with osteosarcoma risk in the Spanish population

Association studies in osteosarcoma risk found significant results in intergenic regions, suggesting that regions which do not codify for proteins could play an important role. The deregulation of microRNAs (miRNAs) has been already associated with osteosarcoma. Consequently, genetic variants affecting miRNA function could be associated with risk. This study aimed to evaluate the involvement of all genetic variants in pre-miRNAs described so far in relationship to the risk of osteosarcoma. We analyzed a total of 213 genetic variants in 206 pre-miRNAs in two cohorts of osteosarcoma patients (n = 100) and their corresponding controls (n = 256) from Spanish and Slovenian populations, using Goldengate Veracode technology (Illumina). Four polymorphisms in pre-miRNAs at 14q32 miRNA cluster were associated with osteosarcoma risk in the Spanish population (rs12894467, rs61992671, rs58834075 and rs12879262). Pathway enrichment analysis including target genes of these miRNAs pointed out the WNT signaling pathways overrepresented. Moreover, different single nucleotide polymorphism (SNP) effects between the two populations included were observed, suggesting the existence of population differences. In conclusion, 14q32 miRNA cluster seems to be a hotspot for osteosarcoma susceptibility in the Spanish population, but not in the Slovenian, which supports the idea of the existence of population differences in developing this disease.Special thanks to Slovenian Osteosarcoma Study Group for their collaboration in sample collection. The "Slovenian Osteosarcoma Study Group" is conformed by Katja Goricar from the Institute of Biochemistry, Faculty of Medicine of Ljubljana, Viljem Kovac from the Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine of University of Ljubljana, Janez Jazbec from the Institute of Oncology Ljubljana, Janez Lamovec from the Oncology and Hematology Unit, University Children's Hospital, University Medical Centre of Ljubljana and Prof. Vita Dolzan included in the authorship of this article. The authors would like to thank Leire Iparraguirre for her technical assistance with figures. This study was funded by the Basque Government (IT661-13, IT989-16), UPV/EHU (UFI11/35)

Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia

Objectives Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Treviño and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity. The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL. Methods We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol. Results A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519 in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated. Conclusion Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.This project was supported by RTICC (RD/06/0020/0048), Basque Government (GIC10/71, SAI11/75, SAI10/03), and UPV/EHU (UFI11/35). E.L.L. was supported by a predoctoral grant from the Basque Government

Confirmation of involvement of new variants at CDKN2A/B in pediatric acute lymphoblastic leukemia susceptibility in the Spanish population

The locus CDKN2A/B (9p21.3), which comprises the tumor suppressors genes CDKN2A and CDKN2B and the long noncoding RNA (lncRNA) known as ANRIL (or CDKN2B-AS), was associated with childhood acute lymphoblastic leukemia (ALL) susceptibility in several genome wide association studies (GWAS). However, the variants associated in the diverse studies were different. Recently, new and independent SNPs deregulating the locus function were also identified in association with ALL risk. This diversity in the results may be explained because different variants in each population could alter CDKN2A/B locus function through diverse mechanisms. Therefore, the aim of this study was to determine whether the annotated risk variants in the CDKN2A/B locus affect the susceptibility of B cell precursor ALL (B-ALL) in our Spanish population and explore if other SNPs altering additional regulatory mechanisms could be also involved. We analyzed the four SNPs proposed by GWAs and two additional SNPs in miRNA binding sites in 217 pediatric patients with B-ALL and 330 healthy controls. The SNPs rs2811712, rs3731249, rs3217992 and rs2811709 were associated with B-ALL susceptibility in our Spanish population. ALL subtypes analyses showed that rs2811712 was associated with B-hyperdiploid ALL. These results provide evidence for the influence of genetic variants at CDKN2A/B locus with the risk of developing BALL.This study was funded by the Basque Government (IT661-13, IT989-16), UPV/EHU (UFI11/35). AGC was supported by a pre-doctoral grant from the Basque Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Involvement of SNPs in miR-3117 and miR-3689d2 in Childhood Acute Lymphoblastic Leukemia Risk

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Numerous studies have shown that microRNAs (miRNAs) could play a role in this disease. Nowadays, more than 2500 miRNAs have been described, that regulate more than 50% of genes, including those involved in B-cell maturation, differentiation and proliferation. Genetic variants in miRNAs can alter their own levels or function, affecting their target gene expression, and then, may affect ALL risk. Therefore, the aim of this study was to determine the role of miRNA genetic variants in B-ALL susceptibility. We analyzed all variants in pre-miRNAs (MAF > 1%) in two independent cohorts from Spain and Slovenia and inferred their functional effect by in silico analysis. SNPs rs12402181 in miR-3117 and rs62571442 in miR-3689d2 were associated with ALL risk in both cohorts, possibly through their effect on MAPK signalling pathway. These SNPs could be novel markers for ALL susceptibility