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4.
Genes Chromosomes Cancer ; 59(9): 540-543, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32306475

RESUMO

In recent years, a subgroup of B-cell precursor acute lymphoblastic leukemia (BCP ALL) without an established abnormality ("B-other") has been shown to be characterized by rearrangements of ABL1, ABL2, CSF1R, or PDGFRB (a.k.a. ABL-class genes). Using FISH with probes for these genes, we screened 55 pediatric and 50 adult B-other cases. Three (6%) of the adult but none of the childhood B-other cases were positive for ABL-class aberrations. RT-PCR and sequencing confirmed a rare SFPQ-ABL1 fusion in one adult B-other case with t(1;9)(p34;q34). Only six SFPQ-ABL1-positive BCP ALLs have been reported, present case included. A review of these shows that all harbored fusions between exon 9 of SFPQ and exon 4 of ABL1, that the fusion is typically found in adolescents/younger adults without hyperleukocytosis, and that IKZF1 deletions are recurrent. The few patients not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation relapsed, strengthening the notion that TKI should be added to the therapy of SFPQ-ABL1-positive BCP ALL.


Assuntos
Proteínas de Fusão Oncogênica/genética , Fator de Processamento Associado a PTB/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-abl/genética , Adolescente , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Fator de Transcrição Ikaros/genética , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/uso terapêutico
5.
Pediatr Blood Cancer ; 66(1): e27437, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30216644

RESUMO

Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hyperglycaemia, need for mechanical ventilation, pseudocysts, and death. Here, we provide novel data on seven patients diagnosed with diabetes after pancreatitis and still requiring insulin treatment after a median follow-up of 4.2 years (range: 1.7-9.2). We describe the clinical course of pancreatitis and illustrate the association between pancreatic pseudocysts, older age, and development of insulin-dependent diabetes. Together, this study documents the persisting burden of pancreatitis in childhood ALL and underlines the need for plasma glucose level monitoring.


Assuntos
Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Diabetes Mellitus Tipo 1/etiologia , Pancreatite/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Doença Aguda , Adolescente , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pancreatite/induzido quimicamente , Pancreatite/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Prognóstico
6.
Genes Chromosomes Cancer ; 57(11): 604-607, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30203896

RESUMO

Single nucleotide polymorphism array (SNP-A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP-A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances >5 Mb and microdeletions targeting the BTG1, CDKN2A/B, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T-cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP-A analyses that either revealed additional imbalances >5 Mb or better characterized the changes found by G-banding. Of 260 B-cell precursor (BCP) ALL cases, SNP-A analyses identified additional copy number alterations, including the above-mentioned microdeletions, or better characterized the imbalances found by G-banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41/260 (16%) BCP ALL cases was revised based on the SNP-A findings. Of the subtype revisions, 12/41 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype-specific minimal residual disease stratification. We conclude that SNP-A analyses dramatically improve the cytogenetic characterization of both T-cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Citogenética , Humanos , Lactente , Recém-Nascido , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico
8.
Leukemia ; 32(10): 2117-2125, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29626196

RESUMO

High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.


Assuntos
Metilação de DNA/genética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transcriptoma/genética , Adolescente , Linfócitos B/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Diploide , Éxons/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Masculino , Análise de Sequência de RNA/métodos
9.
Nat Commun ; 7: 11790, 2016 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-27265895

RESUMO

Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease.


Assuntos
Rearranjo Gênico/genética , Proteínas de Homeodomínio/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Processamento Alternativo/genética , Criança , Quebra Cromossômica , Análise por Conglomerados , Estudos de Coortes , Análise Mutacional de DNA , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Análise de Componente Principal
10.
Br J Haematol ; 174(2): 292-301, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27022003

RESUMO

Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFB-MYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed ≥1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML.


Assuntos
Análise Citogenética/métodos , Éxons/genética , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/diagnóstico , Mutação , Nucleofosmina , Análise de Sequência de DNA
11.
Oncotarget ; 6(40): 42793-802, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26544893

RESUMO

PURPOSE: To investigate the genetic and epigenetic landscape of hypodiploid (<45 chromosomes) acute lymphoblastic leukemia (ALL). METHODS: Single nucleotide polymorphism array, whole exome sequencing, RNA sequencing, and methylation array analyses were performed on eleven hypodiploid ALL cases. RESULTS: In line with previous studies, mutations in IKZF3 and FLT3 were detected in near-haploid (25-30 chromosomes) cases. Low hypodiploidy (31-39 chromosomes) was associated with somatic TP53 mutations. Notably, mutations of this gene were also found in 3/3 high hypodiploid (40-44 chromosomes) cases, suggesting that the mutational patterns are similar in low hypodiploid and high hypodiploid ALL. The high hypodiploid ALLs frequently displayed substantial cell-to-cell variability in chromosomal content, indicative of chromosomal instability; a rare phenomenon in ALL. Gene expression analysis showed that genes on heterodisomic chromosomes were more highly expressed in hypodiploid cases. Cases clustered according to hypodiploid subtype in the unsupervised methylation analyses, but there was no association between chromosomal copy number and methylation levels. A comparison between samples obtained at diagnosis and relapse showed that the relapse did not arise from the major diagnostic clone in 3/4 cases. CONCLUSIONS: Taken together, our data support the conclusion that near-haploid and low hypodiploid ALL are different with regard to mutational profiles and also suggest that ALL cases with high hypodiploidy may harbor chromosomal instability.


Assuntos
Aneuploidia , Epigênese Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma/genética , Cariótipo Anormal , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
J Hematol Oncol ; 8: 42, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25903014

RESUMO

BACKGROUND: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations, subsequently giving rise to a malignant, clonal expansion of T-lymphoblasts. The aim of the present study was to identify additional as well as cooperative genetic events in T-ALL. METHODS: A population-based pediatric T-ALL series comprising 47 cases was investigated by SNP array and deep sequencing analyses of 75 genes, in order to ascertain pathogenetically pertinent aberrations and to identify cooperative events. RESULTS: The majority (92%) of cases harbored copy number aberrations/uniparental isodisomies (UPIDs), with a median of three changes (range 0-11) per case. The genes recurrently deleted comprised CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. No case had a whole chromosome UPID; in fact, literature data show that this is a rare phenomenon in T-ALL. However, segmental UPIDs (sUPIDs) were seen in 42% of our cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse; thus, such mutations can be secondary events. CONCLUSIONS: Deep sequencing and SNP array analyses of T-ALL revealed lack of wUPIDs, a high proportion of sUPID9p targeting CDKN2A, NOTCH1 mutations in subclones, and recurrent mutations of genes involved in signaling transduction, epigenetic regulation, and transcription.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Receptor Notch1/genética , Feminino , Humanos , Incidência , Masculino , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Dissomia Uniparental
13.
Genes Chromosomes Cancer ; 54(5): 315-25, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25727050

RESUMO

In contrast to IKZF1 deletions (ΔIKZF1), IKZF1 sequence mutations (mutIKZF1) have been reported to be rare in B-cell precursor acute lymphoblastic leukemia and their clinical implications are unknown. We performed targeted deep sequencing of all exons of IKZF1 in 140 pediatric cases, eight (5.7%) of which harbored a mutIKZF1. The probabilities of relapse (pRel) and event-free survival (pEFS) did not differ between cases with or without mutIKZF1, whereas pEFS was decreased and pRel increased in ΔIKZF1-positive case. Coexisting microdeletions, mutations (FLT3, JAK2, SH2B3, and SPRED1), and rearrangements (ABL1, CRLF2, JAK2, and PDGFRB) in 35 ΔIKZF1 and/or mutIKZF1-positive cases were ascertained using fluorescence in situ hybridization, single nucleotide polymorphism array, Sanger, and targeted deep sequencing analyses. The overall frequencies of copy number alterations did not differ between cases with our without ΔIKZF1/mutIKZF1. Deletions of HIST1, SH2B3, and the pseudoautosomal region (PAR1), associated with deregulation of CRLF2, were more common in ΔIKZF1-positive cases, whereas PAR1 deletions and JAK2 mutations were overrepresented in the combined ΔIKZF1/mutIKZF1 group. There was no significant impact on pRel of the deletions in ΔIKZF1-positive cases or of JAK2 mutations in cases with ΔIKZF1/mutIKZF1. In contrast, the pRel was higher (P = 0.005) in ΔIKZF1/mutIKZF1-positive cases with PAR1 deletions.


Assuntos
Fator de Transcrição Ikaros/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Deleção de Sequência , Adolescente , Sequência de Bases , Criança , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico
14.
Pediatr Blood Cancer ; 61(3): 424-30, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24424791

RESUMO

BACKGROUND: In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis. PROCEDURE: We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes. RESULTS: Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen. CONCLUSIONS: Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Pré-Escolar , Proteína 7 com Repetições F-Box-WD , Feminino , Genes myb , Proteínas de Homeodomínio/genética , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Prognóstico , Fatores de Transcrição HES-1
15.
PLoS One ; 8(6): e65373, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23762353

RESUMO

BACKGROUND: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided. DESIGN AND METHODS: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32). RESULTS: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes. CONCLUSIONS: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.


Assuntos
Ilhas de CpG , Regulação Leucêmica da Expressão Gênica , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Regiões Promotoras Genéticas , Adolescente , Criança , Pré-Escolar , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Análise Multivariada , Proteínas de Neoplasias/metabolismo , Fenótipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Análise de Sobrevida
16.
Genes Chromosomes Cancer ; 52(4): 370-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23225516

RESUMO

Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC translocations t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11;q24) in 60%-80% of Burkitt lymphomas/leukemias (BL). The high incidence of such aberrations indicates that additional changes are important, perhaps necessary, for malignant transformation, i.e., the 8q24/MYC rearrangements may not be sufficient. To investigate this possibility, we performed single nucleotide polymorphism (SNP) array analysis on 20 cases of 8q24/MYC-positive BL. Nineteen (95%) harbored genomic imbalances; the only case without such aberrations displayed secondary changes by chromosome banding analysis. Thus, all BL cases had abnormalities in addition to the 8q24 translocation. The adult cases harbored more changes (median 3; range 1-21) than did the childhood cases (median 1.5; range 0-5) (P = 0.034). Several recurrent aberrations were detected by SNP array analysis, in particular losses of 6q14.1-q22.33, 9p21.3, and 13q14.2-q14.3, gains of 1q23.3-q31.3, chromosome 7, 13q31.3, and partial uniparental isodisomies for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. The molecular genetic consequences of these changes include deletions of the CDKN2A and TP53 genes, and gains/losses of several genes, such as MIR17HG and E2F2K, involved in the MYC pathway. Thus, deregulation of the MYC pathway, both directly through the 8q24/MYC translocation and indirectly through secondary genomic imbalances, may be essential not only for the initiation but also for the progression of BL.


Assuntos
Linfoma de Burkitt/genética , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Leucemia/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Linfoma de Burkitt/patologia , Criança , Pré-Escolar , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia/patologia , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Adulto Jovem
17.
Genes Chromosomes Cancer ; 51(2): 196-206, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22072402

RESUMO

Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as <10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrent-dup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.


Assuntos
Síndrome de Down/genética , Deleção de Genes , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Síndrome de Down/complicações , Feminino , Estudos de Associação Genética , Humanos , Lactente , Leucemia Mieloide/complicações , Leucemia Mieloide/genética , Masculino , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
18.
Br J Haematol ; 152(6): 743-53, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21250970

RESUMO

Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0·1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of ≥0·1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ-PCR, a higher MRD cut-off (≥0·2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of ≥0·1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Citometria de Fluxo/métodos , Seguimentos , Humanos , Lactente , Masculino , Neoplasia Residual , Reação em Cadeia da Polimerase/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Análise de Sobrevida
19.
Acta Paediatr ; 100(5): 750-7, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21158910

RESUMO

AIM: Solid tumours constitute 40% of childhood malignancies. The Swedish Childhood Cancer Registry is population based and includes all children with cancer reported from the six paediatric oncology centres in Sweden. The aim was to investigate incidence and survival. METHODS: We used the new WHO ICCC-3 for reclassification of the patients. Incidence and survival analyses were performed in the study population. RESULTS: Two thousand four hundred and eighty-seven children (<15 years) were diagnosed with solid tumours in Sweden between 1983 and 2007. The distribution of diagnoses was similar to that reported in other studies. The annual incidence was 65.3 per million children. The survival rates at 10 years of follow-up have improved significantly when comparing the two time periods, 1983-1995 and 1995-2007 (76 vs. 82%; p < 0.01). CONCLUSIONS: The mean annual incidence of solid tumours in children was 65.3/million and has been stable during the study period. Survival rates for solid tumours at 5, 10 and 20 years follow-up were 80, 79 and 76%, respectively.


Assuntos
Neoplasias/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Masculino , Neoplasias/diagnóstico , Neoplasias/mortalidade , Sistema de Registros , Análise de Sobrevida , Taxa de Sobrevida/tendências , Suécia/epidemiologia
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