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1.
Epigenomics ; 12(1): 69-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31833405

RESUMO

Despite remarkable improvements in survival of childhood acute lymphoblastic leukemia (ALL), nonresponding or relapsing patients still represent one of the most frequent causes of death by disease in children. Accurate patient risk stratification based on genetic markers could increases survival rates. miRNAs can represent novel candidates with diagnostic, predictive and prognostic potential; however, many groups investigated their involvement with contradictory results. Aim: To clarify the role of miRNAs as biomarkers through a systematic review. Results: From a revision of 45 manuscripts, we found that miR-128 and miR-181 overexpression could represent markers for ALL diagnosis and underexpression of miR-708 and miR-99a could be markers for bad prognosis. Conclusion: These signatures could refine classification and risk stratification of patients and improve ALL outcome.

2.
Theranostics ; 9(16): 4567-4579, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31367240

RESUMO

Cerebrospinal fluid (CSF) microRNAs (miRNAs) have emerged as potential biomarkers for minimally invasive diagnosis of central nervous system malignancies. However, despite significant advances in recent years, this field still suffers from poor data reproducibility. This is especially true in cases of infants, considered a new subject group. Implementing efficient methods to study miRNAs from clinically realistic CSF volumes is necessary for the identification of new biomarkers. Methods: We compared six protocols for characterizing miRNAs, using 200-µL CSF from infants (aged 0-7). Four of the methods employed extracellular vesicle (EV) enrichment step and the other two obtained the miRNAs directly from cleared CSF. The efficiency of each method was assessed using real-time PCR and small RNA sequencing. We also determined the distribution of miRNAs among different CSF shuttles, using size-exclusion chromatography. Results: We identified 281 CSF miRNAs from infants. We demonstrated that the miRNAs could be efficiently detected using only 200 µL of biofluid in case of at least two of the six methods. In the exosomal fraction, we found 12 miRNAs that might be involved in neurodevelopment. Conclusion: The Norgen and Invitrogen protocols appear suitable for the analysis of a large number of miRNAs using small CSF samples.

3.
Mol Neurobiol ; 56(12): 8376-8391, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31240600

RESUMO

Late-onset Alzheimer's disease (LOAD) is a high-occurrence neurological disorder but the difficulty in identifying precise and early biomarkers has complicated the understanding of the disease and the development of new treatments. In this sense, important knowledge is emerging regarding novel molecular and biological candidates with diagnostic potential, including microRNAs (miRNAs), which have a key role in gene repression. The aim of this systematic review was to define the role of miRNAs' expression as biomarkers for LOAD both in brain tissues, which could help understand the biology of the disease, and circulating tissues, which could serve as non-invasive markers of the pathology. A systematic search was performed in Web of Science and PubMed using the keywords ((Alzheimer or Alzheimer's) and (microRNA or microRNAs or miRNA or miRNAs or miR)) until August 2018 to retrieve all articles that presented independent original data evaluating the impact of miRNA expression on the development of LOAD in human population. A total of 90 studies investigating the role of miRNAs' expression in the development of LOAD were identified. While other widely studied miRNAs such as hsa-miR-146a presented contradictory results among studies, deregulation in brain tissue of seven miRNAs, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-107, hsa-miR-125-5p, hsa-miR-132-3p, hsa-miR-181-3p, and hsa-miR-212-3p, was consistently identified in LOAD patients. Their role in the disease could be mediated through the regulation of key pathways, such as axon guidance, longevity, insulin, and MAPK signaling pathway. However, regarding their role as non-invasive biomarkers of LOAD in fluids, although the limited results available are promising, further studies are required.

4.
Crit Rev Oncol Hematol ; 139: 7-15, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31112884

RESUMO

Cell-free DNA (cfDNA), which is DNA released from cells into the circulation, is one of the most promising non-invasive biomarkers in cancer. This approach could be of interest for the management of Diffuse Large B-Cell Lymphoma (DLBCL) patients, which is the most common non-Hodgkin lymphoma. Then, the aim of this systematic review was to define the utility of cfDNA in this disease. Selected articles were classified in four groups, depending on the aspects of cfDNA studied, i.e. concentration, methylation, IgH gene rearrangements, and somatic mutations. While concentration and methylation of cfDNA need to be further analyzed, IgH gene rearrangements and somatic mutations seem to be the most promising biomarkers to date. Their detection has been shown to allow disease monitoring and early prediction of relapse. Although more efforts and standardization of techniques are needed, studying cfDNA in liquid biopsy may help improve the outcome of DLBCL patients.


Assuntos
Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Ácidos Nucleicos Livres/sangue , Humanos , Biópsia Líquida , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/genética , Prognóstico
5.
Pharmacogenomics J ; 19(6): 564-569, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30723315

RESUMO

Vincristine is an important drug of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. A genetic variant in CEP72, a gene involved in vincristine pharmacodynamics, was recently associated with neurotoxicity after prolonged vincristine treatment. This association was not replicated in our Spanish population during induction phase. To test the possibility that other variants in genes involved in vincristine pharmacodynamics were associated with vincristine neuropathy in early phases of the treatment, we evaluated the correlation with toxicity of 24 polymorphisms in 9 key genes in a large cohort of 152 Spanish children with B-ALL homogeneously treated. Results showed no association between any genetic variant in the TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4, MAPT, MIR146a, MIR202, and MIR411 genes and vincristine-related neurotoxicity. These results are in line with the hypothesis that there are different mechanisms causing pheripheral neurotoxicity after prolonged and short-term vincristine treatments.

6.
Arch Gynecol Obstet ; 299(4): 901-921, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30671700

RESUMO

PURPOSE: The aim of this study was to clarify whether physical activity may be associated with semen quality, considering the different types of sports, their intensity, and the semen parameters studied in the literature. METHODS: Eligible studies included those that evaluated the impact of physical activity in semen parameters in human population. Outcomes evaluated included the following seminal quality parameters: volume, concentration, total sperm count, progressive motility, total motility, total motile sperm count, morphology, and motile sperm concentration. RESULTS: We identified 32 manuscripts that analyzed this effect. Among them, 20 articles examined the role of general physical activity and 17 analyzed this relationship among specific sports. Although most results point to a lack of major effects of physical activity on semen quality, recreational physical activity could have a positive effect on semen concentration or progressive motility. On the contrary, elite physical activity could be detrimental for some semen parameters, such as progressive motility. Regarding specific sports, a negative effect of cycling on semen concentration is suggested. CONCLUSIONS: In conclusion, recreational physical activity seems to be of benefit for men with infertility issues. However, elite physical activity could have a detrimental effect on semen quality, which should be taken into consideration.

7.
Cancers (Basel) ; 11(2)2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30691158

RESUMO

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.

9.
Pharmacogenomics ; 19(18): 1403-1412, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30479191

RESUMO

AIM: Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokinetic/pharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokinetic/pharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk. PATIENTS & METHODS: We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LAL/SHOP protocols. RESULTS: We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively. CONCLUSION: The effect of these SNPs on genes related to drug pharmacokinetics/pharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Mucosite/genética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Estudos Retrospectivos
10.
Sci Rep ; 8(1): 15414, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30337581

RESUMO

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.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Cromossomos Humanos Par 14/genética , MicroRNAs/genética , Osteossarcoma/genética , Polimorfismo de Nucleotídeo Único , Idoso , Neoplasias Ósseas/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Osteossarcoma/epidemiologia , Prognóstico , Fatores de Risco , Espanha/epidemiologia
11.
Oncotarget ; 9(32): 22850-22861, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29854319

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy, with highly variable outcomes among patients. Although classification and prognostic tools have been developed, standard therapy still fails in 30-40% of patients. Hence, identification of novel biomarkers is needed. Recently, circulating microRNAs (miRNAs) have been suggested as non-invasive biomarkers in cancer. Our aim was to review the potential role of circulating miRNAs as biomarkers for diagnosis, classification, prognosis, and treatment response in DLBCL. We performed a search in PubMed using the terms [(('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 identify articles that evaluated the impact of circulating miRNAs as diagnosis, subtype, treatment response or prognosis biomarkers in DLBCL in human population. Among the twelve articles that met the inclusion criteria, eleven considered circulating miRNAs as biomarkers for diagnosis, two for classification, and five for prognosis or treatment response. The limited number of studies performed and lack of consistency in results make it difficult to draw conclusions about the role of circulating miRNAs as non-invasive biomarkers in DLBCL. Although the preliminary associations observed seem promising, the only consistent result is the upregulation of mir-21 in DLBCL patients, which could be a biomarker for diagnosis. Further studies are needed.

12.
Oncotarget ; 9(33): 22907-22914, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29796161

RESUMO

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.

13.
Epigenomics ; 10(4): 409-417, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29569486

RESUMO

AIM: Hepatotoxicity is one of the most common drug-related toxicities during the treatment of childhood acute lymphoblastic leukemia (ALL). Many genes involved in liver-specific signaling pathways are tightly controlled by miRNAs, and miRNA function could be modulated by SNPs. As a consequence, we hypothesized that variants in miRNAs could be associated with drug-induced hepatotoxicity. METHODS: We analyzed 213 SNPs in 206 miRNAs in a cohort of 179 children with ALL homogeneously treated. RESULTS: rs2648841 in miR-1208 was the most significant SNP during consolidation phase after false discovery rate correction, probably through an effect on its target genes DHFR, MTR and MTHFR. CONCLUSION: These results point out the possible involvement of SNPs in miRNAs in toxicity to chemotherapy in children with ALL.


Assuntos
Fígado/efeitos dos fármacos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , MicroRNAs/química , Conformação de Ácido Nucleico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos
14.
Pharmacogenomics ; 19(4): 361-373, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29469670

RESUMO

Childhood acute lymphoblastic leukemia survival rates have increased remarkably during last decades due, in part, to intensive treatment protocols. However, therapy resistance and toxicity are still two important barriers to survival. In this context, pharmacoepigenetics arises as a tool to identify new predictive markers, required to guide clinicians on risk stratification and dose individualization. The present study reviews current evidence about miRNA implication on childhood acute lymphoblastic leukemia therapy resistance and toxicity. A total of 12 studies analyzing differential miRNA expression in relation to drug resistance and six studies exploring the association between miRNAs-related SNPs and drug-induced toxicities were identified. We pointed out to miR-125b together with miR-99a and/or miR-100 overexpression as markers of vincristine resistance and rs2114358 in mir-1206 as mucositis marker as the most promising results.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Humanos , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Taxa de Sobrevida
15.
Pharmacogenomics J ; 18(6): 704-712, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29282364

RESUMO

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , MicroRNAs/genética , Doença dos Neurônios Motores/induzido quimicamente , Doença dos Neurônios Motores/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Transtornos das Sensações/induzido quimicamente , Transtornos das Sensações/genética , Vincristina/efeitos adversos , Transportadores de Cassetes de Ligação de ATP/genética , Idade de Início , Antineoplásicos Fitogênicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Proteínas Ativadoras de GTPase/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Doença dos Neurônios Motores/diagnóstico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Farmacogenética , Testes Farmacogenômicos , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Transtornos das Sensações/diagnóstico , Espanha , Vincristina/administração & dosagem
16.
Med Oncol ; 34(10): 179, 2017 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-28905228

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading cause of death due to disease in children. The genetic basis of ALL susceptibility has been supported by its association with certain congenital disorders and, more recently, by several genome-wide association studies (GWAS). These GWAS identified common variants in ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, LHPP and ELK3 influencing ALL risk. However, the risk variants of these SNPs were not validated in all populations, suggesting that some of the loci could be population specific. On the other hand, the currently identified risk SNPs in these genes only account for 19% of the additive heritable risk. This estimation indicates that additional susceptibility variants could be discovered. In this review, we will provide an overview of the most important findings carried out in genetic susceptibility of childhood ALL in all GWAS and subsequent studies and we will also point to future directions that could be explored in the near future.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Criança , Predisposição Genética para Doença , Humanos
17.
Pharmacogenet Genomics ; 27(8): 303-306, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28628559

RESUMO

Five-year survival rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity because of methotrexate (MTX) occurs frequently. Variety in the occurrence of toxicity is partly determined by single nucleotide polymorphisms (SNPs) in coding regions. Recently, five SNPs in non-coding pre-microRNAs and microRNA processing (miRNA) genes were identified in association with MTX-induced oral mucositis. This study aimed to replicate the association of these miRNA variants in relation to MTX-induced oral mucositis in a prospective childhood ALL cohort. Three out of five SNPs with a minor allele frequency more than 0.15 [CCR4-NOT transcription complex (CNOT4) rs3812265, miR-1206 rs2114358, miR-2053 rs10505168] were analyzed in 117 pediatric ALL patients treated with 5 g/m MTX (DCOG ALL-10). Oral mucositis was defined as grade more than or equal to 3 according to the National Cancer Institute criteria. rs2114358 in miR-1206 was associated with oral mucositis [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.1-11.5], whereas we did not confirm the association of CNOT4 rs3812265 (OR: 0.69; 95% CI: 0.27-1.80) and miR-2053 rs10505168 (OR: 2.50; 95% CI: 0.76-8.24). Our results replicate the association between rs2114358 in miR-1206 and MTX-induced oral mucositis in childhood ALL. Genetic variation in miR-1206 has potential as a novel biomarker to predict MTX-induced toxicity.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Metotrexato/efeitos adversos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estomatite/genética , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , MicroRNAs/química , Conformação de Ácido Nucleico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Prospectivos , Estomatite/induzido quimicamente
18.
PLoS One ; 12(5): e0177421, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28481918

RESUMO

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 B-ALL.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Leucemia de Células B/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Genótipo , Humanos , Lactente , Masculino , Espanha
19.
Pharmgenomics Pers Med ; 10: 69-78, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28392709

RESUMO

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.

20.
Drug Metab Pers Ther ; 32(1): 1-9, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28259867

RESUMO

Acute lymphoblastic leukemia (ALL) is a major pediatric cancer in developed countries. Although treatment outcome has improved owing to advances in chemotherapy, there is still a group of patients who experience severe adverse events. L-Asparaginase is an effective antineoplastic agent used in chemotherapy of ALL. Despite its indisputable indication, hypersensitivity reactions are common. In those cases, discontinuation of treatment is usually needed and anti-asparaginase antibody production may also attenuate asparaginase activity, compromising its antileukemic effect. Till now, six pharmacogenetic studies have been performed in order to elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity. In this review we have summarized the results of those studies which describe the involvement of four different genes, being polymorphisms in the glutamate receptor, ionotropic, AMPA 1 (GRIA1) the most frequently associated with asparaginase hypersensitivity. We also point to new approaches focusing on epigenetics that could be interesting for consideration in the near future.


Assuntos
Asparaginase/metabolismo , Variação Genética/genética , Farmacogenética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de AMPA/genética , Antineoplásicos/uso terapêutico , Predisposição Genética para Doença/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Receptores de AMPA/metabolismo , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo
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