Assuntos
Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Cariótipo Anormal , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Impressão Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Regiões Promotoras Genéticas , Proteínas/genética , Proteínas de Ligação a RNA/genética , Adulto JovemRESUMO
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/diagnósticoAssuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Dissomia Uniparental/genética , Alelos , Aberrações Cromossômicas , Biologia Computacional/métodos , Bases de Dados Genéticas , Variação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Sequenciamento do ExomaRESUMO
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.
