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

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

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

The Role of the Dysregulation of Long Non-Coding and Circular RNA Expression in Medulloblastoma: A Systematic Review

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Although recent multi-omic studies have led to advances in MB classification, there is still room for improvement with regard to treatment response and survival. Therefore, identification of new and less invasive biomarkers is needed to refine the diagnostic process and to develop more personalized treatment strategies. In this context, non-coding RNAs (ncRNAs) could be useful biomarkers for MB. In this article, we reviewed the role of two types of ncRNAs, long non-coding (lncRNAs) and circular RNAs (circRNAs), as biomarkers for the diagnosis, subgroup classification, and prognosis of MB. We also reviewed potential candidates with specific functions and mechanisms of action in the disease. We performed a search in PubMed and Scopus using the terms (“long non coding RNAs” OR ”lncRNAs”) and (“circular RNAs” OR ”circRNAs”) AND ”medulloblastoma” to identify biomarker discovery or functional studies evaluating the effects of these ncRNAs in MB. A total of 26 articles met the inclusion criteria. Among the lncRNAs, the tumorigenic effects of the upregulated lnc-IRX3-80 and lnc-LRRC47-78 were the most studied in MB. Among the circRNAs, the upregulation of circSKA3 and its functional impact in MB cell lines were the most consistent results, so this circRNA could be considered a potential biomarker in MB. Additional validation is required for many deregulated lncRNAs and circRNAs; therefore, further studies are warranted.This research was funded by the Basque Foundation for Health Innovation and Research (IT1559-22) and EiTB Maratoia (Bioef) (BIO20/CI/017). I.M.d.E. was supported by an Ikasiker fellowship and an Asociación Española Contra el Cáncer (AECC) (Prácticas Laboratorio de Verano AECC 2022-2608A48D0E01012) fellowship for his lab internship. A.G.-C. was supported by a postdoctoral fellowship from the Fundación Vasca de Innovación e Investigación Sanitaria (Bioef) (BIO20/CI/016). U.I. was supported by a pre-doctoral contract from UPV/EHU

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 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)

LncRNA-en adierazpen aldakorrak haurren leuzemia linfoblastiko akutuan dituen inplikazioak

Haurren leuzemia linfoblastiko akutua (LLA) minbizi pediatrikorik ohikoena da eta heriotza kausa nagusia 20 urte baino gutxiagoko minbizidun gaixoen artean. Aurrerapen teknologikoei esker sailkapen-zehaztasuna eta sendatze-tasa hobetu diren arren, oraindik ere asko dira birgaixotzen diren pazienteak. Hori dela eta, pazienteen estratifikazio eta tratamendu espezifikoagoen beharra azaleratu da. LLA minbizi oso heterogeneoa da eta azpitalde ezberdin ugari daude. Oraintsu, pazienteen estratifikazioa egiteko, RNA ez-kodetzaileetan jarri da arreta; esaterako, RNA luze ez-kodetzaileetan (lncRNA). Molekula horiek proteinak kodetzen ez dituzten 200 nukleotido baino gehiagoko molekula erribonukleikoak dira, eta frogatu da funtzio erregulatzaile garrantzitsua dutela hainbat prozesu biologikotan, besteak beste hematopoiesian. Azken urteetan ugariak izan dira lncRNAen adierazpen aldakorra LLA pediatrikoan aztertu duten ikerketak. Horietan, sekuentziazio edo array bidezko genoma osoko analisiak eta RT-qPCR bidezko lncRNA zehatzen adierazpena aztertuz, minbizi honen diagnosian, azpitalde ezberdinen sailkapenean, pronostikoan eta tratamenduan duten adierazpen-patroi aldakorra ikertu dute. Hala, zenbait kasutan ondorioztatu da lncRNAk erlazionatuta daudela leuzemia-zelulen proliferazio edo apoptosiarekin, bir-gaixotzeekin edo tratamenduekiko erresistentziarekin. Hori dela eta, dugun informazioa oraindik ere mugatua izan arren, ezinbestekoa izango da lncRNAek mekanismo molekularretan dituzten funtzioak ezagutzea, etorkizunean LLA gaixoen es-tratifikazio zehatza lortzeko eta tratamendu-itu berriak identifikatzeko; Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the leading cause of death among cancer patients under 20 years of age. Although classification accuracy and recovery rates have improved due to technological advances, there are still many patients who relapse. Hence, the development of more accurate patient stratification methods and treatments are essential. ALL is a highly heterogeneous cancer with multiple subtypes. Recently, attention has been focused on non-coding RNA, such as long non-coding RNA (lncRNA). These ribonucleic molecules of more than 200 nucleotides have been proven to have important regulatory functions in various biological processes, including hematopoiesis. In recent years, numerous studies have examined the differential expression of lncRNAs in pediatric ALL. In these studies, whole genome analysis using sequencing and arrays, and analysis of specific lncRNAs by RT-qPCR have been made to investigate the varying pattern of expression in diagnosis, classification of different subtypes, prognosis and treatment of ALL patients. Thus, in some cases lncRNAs were related to proliferation or apoptosis of leukemic cells, relapse and treatment resistance. Therefore, although the information concerning lncRNAs in ALL is still limited, analysing the functions of lncRNAs in molecular mechanisms will be essential in the near future for the precise stratification of ALL pediatric patients and the identification of novel treatment targets

Polimorfismo genetikoen analisien meta-analisien erabilgarritasunaren analisi kritikoa

Azken urteotan sortzen ari den itzelezko argitalpen kopurua ikusita, meta-analisiak plazaratzen ari dira, helburu bera duten ikerketa lanen informazioa laburtzeko. Hain zuzen ere, gai jakin baten ikerketa lan desberdinen emaitzak konbinatu nahi dira meta-analisi hauetan erantzunik gabeko galderak argitzeko. Kalitatezko meta-analisiak izateko , berau egiteko pausu guztiak ondo landuta eta deskribatuta egon behar dute. Horregatik, meta-analisien erabilgarritasuna baloratzeko haien irakurketa kritikoa egitea oso beharrezkoa da. Adibide moduan, Liu eta laguntzaileak eta gure taldeak, zenbait ahulezi topatu genituen Wang eta laguntzaileek duela gutxi nazioarteko aldizkari zientifiko batean argitaratutako meta-analisian. Ikerketa lan honetan Wang eta laguntzaileen meta-analisiaren irakurketa kritikoa, literaturaren eguneraketa eta asoziazio ikerketa egin genuen . Wang eta laguntzaileak polimorfismoak osteosarkomaren suszeptibi latearekin asoziatuta zeudela ondorioztatu zuten bitartean, gure kasuan ez genuen asoziaziorik topatu . Hortaz, gure lanaren arabera, polimorfismo hauek osteosarkomaren suszeptibilitatearen markatzaile genetikoak ez direla ondorioztatu genuen. Bide batez, adibide honekin, gaur eguneko meta-analisien irakurketa sakona eta analisien emaitzak zuhur hartu behar ditugula azpimarratu nahi dugu, zenbait lanetan ez baitituzte ezarritako irizpideak betetzen mota honetako ikerketa lanak egiterako orduan

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