RESUMEN
ETV6-RUNX1 fusion [t(12;21)(p13;q22)] occurs in 25% of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and is associated with a favorable outcome. Additional abnormalities involving der(21)t(12;21) and nonrearranged chromosome 12 are well characterized but aberrations involving the der(12)t(12;21) have rarely been described. Herein, we describe two novel abnormalities affecting the der(12)t(12;21): a deletion (20/247, 8%) and duplication (10/247, 4%). All 30 patients were under 10 years of age, had a median white blood count of 12.4 × 10(9)/L and 19.2 × 10(9)/L, respectively, with a good outcome. Deletions of der(12)t(12;21) on both sides of the breakpoint were confirmed and mapped: centromeric (12p11.21-12p13.2) and telomeric (21q22.12-21q22.3). The size of these deletions extended from 0.4-13.4 to 0.8-2.5 Mb, respectively. The centromeric deletion encompassed the following genes: LRP6, BCL2L14, DUSP16, CREBL2, and CDKN1B. We postulate that this deletion occurs at the same time as the translocation because it was present in all ETV6-RUNX1-positive cells. A second abnormality representing duplication of the reciprocal RUNX1-ETV6 fusion gene was a secondary event, which we hypothesize arose through mitotic recombination errors. This led to the formation of the following chromosome: der(12)(21qterâ21q22.12::12p13.2-12p12.3::12p12.3â12qter). Both abnormalities affect the reciprocal RUNX1-ETV6 fusion product which could either eliminate or amplify its expression and thus contribute to leukemogenesis. However, other consequences such as haploinsufficiency of tumor suppressor genes and amplification of oncogenes could also be driving forces behind these aberrations. In conclusion, this study has defined novel abnormalities in ETV6-RUNX1 BCP-ALL, which implicate new genes involved in leukemogenesis.
Asunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 21/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética , Centrómero/genética , Niño , Preescolar , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Fosfatasas de Especificidad Dual/genética , Femenino , Duplicación de Gen , Humanos , Hibridación Fluorescente in Situ , Lactante , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Masculino , Análisis por Micromatrices/métodos , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Reacción en Cadena de la Polimerasa Multiplex , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-bcl-2/genética , Telómero/genéticaRESUMEN
In childhood B-cell precursor acute lymphoblastic leukemia, cytogenetics is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment. Little is known of the relationship between different cytogenetic subtypes in B-cell precursor acute lymphoblastic leukemia and the recently reported copy number abnormalities affecting significant leukemia associated genes. In a consecutive series of 1427 childhood B-cell precursor acute lymphoblastic leukemia patients, we have determined the incidence and type of copy number abnormalities using multiplex ligation-dependent probe amplification. We have shown strong links between certain deletions and cytogenetic subtypes, including the novel association between RB1 deletions and intrachromosomal amplification of chromosome 21. In this study, we characterized the different copy number abnormalities and show heterogeneity of PAX5 and IKZF1 deletions and the recurrent nature of RB1 deletions. Whole gene losses are often indicative of larger deletions, visible by conventional cytogenetics. An increased number of copy number abnormalities is associated with NCI high risk, specifically deletions of IKZF1 and CDKN2A/B, which occur more frequently among these patients. IKZF1 deletions and rearrangements of CRLF2 among patients with undefined karyotypes may point to the poor risk BCR-ABL1-like group. In conclusion, this study has demonstrated in a large representative cohort of children with B-cell precursor acute lymphoblastic leukemia that the pattern of copy number abnormalities is highly variable according to the primary genetic abnormality.
Asunto(s)
Análisis Citogenético/métodos , Eliminación de Gen , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Análisis Citogenético/clasificación , Variaciones en el Número de Copia de ADN , Femenino , Heterogeneidad Genética , Humanos , Factor de Transcripción Ikaros/genética , Lactante , Masculino , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adulto JovenAsunto(s)
Vigilancia Inmunológica , Lesiones Precancerosas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Adolescente , Biomarcadores , Biopsia , Médula Ósea , Niño , Preescolar , Evolución Clonal/genética , Evolución Clonal/inmunología , Femenino , Reordenamiento Génico , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Translocación GenéticaRESUMEN
Intellectual disability (ID) is the most common diagnosis noted among children with genetic disorders. It causes social and economic burden to families and communities. The genetic causes are not completely understood, and there is significant heterogeneity. Recently, a new chromosomal X-linked syndrome was reported to cause ID. Four males were described from three families with ID, developmental delay, hypotonia, joint hypermobility, and relative macrocephaly. They all carried small, overlapping Xp11.22 deletions. To date, the described smallest region of overlapping deletion at this locus spanned ~ 430 kb) and included four genes (CENPVL1, CENPVL2, MAGED1, and GSPT2), which are proposed as the main drivers of the phenotype. We describe a male patient who matches the phenotype and contributes to defining a narrow phenocritical region at Xp11.22. We propose that GSPT2 loss-of-function might be the probable cause of the phenotypic features seen in these patients.