RESUMEN
In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3-CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16-75) years. AML was de novo in 58%, therapy-related (t-AML) in 37% and secondary after myelodysplastic syndrome (s-AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3-CREBBP, whole-genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9-1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow-up was 5·48 years; five-year survival rate was 17%. Patients with s-/t-AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo-HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo-HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo-HCT in CR1 was effective in de novo AML but not in patients with s-AML/t-AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo-HCT performed in CR1.
Asunto(s)
Cromosomas Humanos Par 16/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Leucemia Mieloide Aguda/genética , Translocación Genética , Cariotipo Anormal , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Quimioterapia de Consolidación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Cooperación Internacional , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/epidemiología , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/epidemiología , Proteínas de Fusión Oncogénica/genética , Inducción de Remisión , Análisis de Supervivencia , Secuenciación Completa del GenomaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Ciclina D1/genética , Genes myc , Linfoma de Células del Manto/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Cariotipo Anormal , Adenina/análogos & derivados , Anciano , Clorhidrato de Bendamustina/administración & dosificación , Biomarcadores de Tumor , Bortezomib/administración & dosificación , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 8/genética , Citarabina/administración & dosificación , Resistencia a Antineoplásicos , Resultado Fatal , Duplicación de Gen , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Masculino , Piperidinas , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Recurrencia , Rituximab/administración & dosificaciónRESUMEN
Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype.
Asunto(s)
Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/ultraestructura , Neutropenia/genética , Úlceras Bucales/genética , Estomatitis Aftosa/genética , Preescolar , Aberraciones Cromosómicas , Trastornos de los Cromosomas/genética , Citogenética , Femenino , Marcadores Genéticos , Genotipo , Humanos , Cariotipificación , Linfocitos/metabolismo , Metafase , Mosaicismo , Neutropenia/complicaciones , Neutropenia/diagnóstico , Análisis de Secuencia por Matrices de Oligonucleótidos , Úlceras Bucales/complicaciones , Úlceras Bucales/diagnóstico , Fenotipo , Estomatitis Aftosa/complicaciones , Estomatitis Aftosa/diagnósticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Linfocitos/patología , Linfoma de Células B de la Zona Marginal/genética , Neoplasias del Bazo/genética , Translocación Genética , Cariotipo Anormal , Clorhidrato de Bendamustina/administración & dosificación , Linaje de la Célula , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 8/genética , Progresión de la Enfermedad , Femenino , Genes de Inmunoglobulinas , Genes myc , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/patología , Persona de Mediana Edad , Inducción de Remisión , Rituximab/administración & dosificación , Neoplasias del Bazo/tratamiento farmacológico , Neoplasias del Bazo/patología , TrisomíaRESUMEN
Chronic lymphocytic leukemia (CLL) with 17p deletion (17p-) is associated with a lack of response to standard treatment and thus the worst possible clinical outcome. Various chromosomal abnormalities (including unbalanced translocations, deletions, ring chromosomes and isochromosomes) result in the loss of 17p and one copy of the TP53 gene. The objective of the present study was to determine whether the type of chromosomal abnormality leading to 17p- and the additional aberrations influenced the prognosis in a series of 195 patients with 17p-CLL. Loss of 17p resulted primarily from an unbalanced translocation (70%) with several chromosome partners (the most frequent being chromosome 18q), followed by deletion 17p (23%), monosomy 17 (8%), isochromosome 17q [i(17q)] (5%) and a ring chromosome 17 (2%). In a univariate analysis, monosomy 17, a highly complex karyotype (≥5 abnormalities), and 8q24 gain were associated with poor treatment-free survival, and i(17q) (P = .04), unbalanced translocations (P = .03) and 8q24 gain (P = .001) were significantly associated with poor overall survival. In a multivariate analysis, 8q24 gain remained a significant predictor of poor overall survival. We conclude that 17p deletion and 8q24 gain have a synergistic impact on outcome, and so patients with this "double-hit" CLL have a particularly poor prognosis. Systematic, targeting screening for 8q24 gain should therefore be considered in cases of 17p- CLL.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 17/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Leucemia Linfocítica Crónica de Células B/genética , Translocación Genética , Trisomía , Cariotipo Anormal , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Genes p53 , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Pronóstico , Estudios RetrospectivosAsunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Neoplasias Primarias Múltiples/genética , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Cariotipo Anormal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bandeo Cromosómico , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 15/ultraestructura , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 17/ultraestructura , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 21/ultraestructura , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/ultraestructura , Células Clonales/química , Células Clonales/patología , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/patología , Células Madre Neoplásicas/química , Células Madre Neoplásicas/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Translocación GenéticaAsunto(s)
Crisis Blástica/patología , Médula Ósea/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Adulto , Antineoplásicos/uso terapéutico , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/genética , Cromosomas Humanos Par 8/ultraestructura , Genes myc , Humanos , Mesilato de Imatinib/uso terapéutico , Hibridación Fluorescente in Situ , Isocromosomas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/uso terapéuticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cromosomas Humanos Par 16/ultraestructura , Cromosomas Humanos Par 21/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Leucemia Mieloide Aguda/inducido químicamente , Neoplasias Primarias Secundarias/inducido químicamente , Translocación Genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor de Unión a CCAAT/genética , Inversión Cromosómica , Terapia Combinada , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Citarabina/administración & dosificación , Citarabina/efectos adversos , Femenino , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Cadenas Pesadas de Miosina/genética , Neoplasias Primarias Secundarias/genética , Proteínas de Fusión Oncogénica/genética , Trasplante de Células Madre de Sangre Periférica , Proteína 1 Compañera de Translocación de RUNX1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante AutólogoAsunto(s)
Linfoma de Burkitt/patología , Riñón/patología , Infiltración Leucémica/orina , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Orina/citología , Antígenos CD34/análisis , Antígenos de Neoplasias/análisis , Linfoma de Burkitt/genética , Linfoma de Burkitt/orina , Sistema Nervioso Central/patología , Niño , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , ADN Nucleotidilexotransferasa , Humanos , Riñón/diagnóstico por imagen , Infiltración Leucémica/patología , Imagen por Resonancia Magnética , Masculino , Células Madre Neoplásicas/química , Tomografía de Emisión de Positrones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/orina , Translocación Genética , Síndrome de Lisis TumoralRESUMEN
BACKGROUND: The optimal monitoring schedules and cutoff minimal residual disease (MRD) levels for the accurate prediction of relapse at all time points after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with t(8;21) acute myeloid leukemia (AML). METHODS: RUNX1-RUNX1T1 transcript levels were measured in bone marrow samples collected from 208 patients at scheduled time points after transplantation (1530 samples in total). RESULTS: A total of 92.3% of the requested samples were collected, and 74.0% of patients had complete sample collection. The 1-, 3-, and 6-month RUNX1-RUNX1T1 transcript levels could significantly discriminate between continuous complete remission and a hematologic relapse at 1.5-3, 4-6, and 7-12 months but not at >3, >6, and >12 months, respectively. Over 90% of the 175 patients who were in continuous complete remission had a ≥3-log reduction in RUNX1-RUNX1T1 transcript levels from the time of diagnosis at each time point after transplantation and a ≥4-log reduction at ≥12 months. A <3-log reduction within 12 months and/or a <4-log reduction at ≥12 months was significantly related to a higher 3-year cumulative incidence of relapse (CIR) rate in both the entire cohort and the patients with no intervention after HSCT (58.4 vs. 2.2%, 76.5 vs. 2.0%; all P < 0.0001). Patients who had received a preemptive donor lymphocyte infusion when the increase in RUNX1-RUNX1T1 transcripts was ≤1-log according to the above dual cutoff values had significantly lower 1-year CIR rate after intervention than the patients who had received an infusion when the increase was >1-log (0 vs. 55.0%, P = 0.015). CONCLUSIONS: RUNX1-RUNX1T1 transcripts with a <3-log reduction from diagnosis within 12 months and/or a <4-log reduction at ≥12 months after allo-HSCT could accurately predict relapse and may prompt a timely intervention in patients with t(8;21) AML.
Asunto(s)
Cromosomas Humanos Par 21/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Subunidad alfa 2 del Factor de Unión al Sitio Principal/biosíntesis , Regulación Leucémica de la Expresión Génica , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/biosíntesis , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Proteína 1 Compañera de Translocación de RUNX1/biosíntesis , Translocación Genética , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Neoplasia Residual , Proteínas de Fusión Oncogénica/genética , ARN Mensajero/genética , ARN Neoplásico/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Recurrencia , Adulto JovenRESUMEN
It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations-single nucleotide variants (SNVs) or small insertions and deletions (indels)-with probable functional impacts. With aCGH, we identified, in both siblings, a duplication in the 4p16.3 region and a deletion at 8p23.3, inherited by a paternal balanced translocation, t(4, 8) (p16; p23). Exome variant analysis found a total of 316 variants, of which 102 were shared by both siblings, 128 were in the male sibling exome data, and 86 were in the female exome data. Our integrative network analysis showed that the siblings' shared translocation could explain their similar syndromic phenotype, including overgrowth, macrocephaly, and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, which are important to the robustness of the network and contribute to the understanding of the broader spectrum of psychiatric symptoms. This study shows the importance of using an integrative approach to explore genotype-phenotype variability.
Asunto(s)
Trastorno del Espectro Autista/genética , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 8/genética , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Exoma/genética , Estudios de Asociación Genética , Translocación Genética , Niño , Cromosomas Humanos Par 4/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Femenino , Duplicación de Gen , Redes Reguladoras de Genes , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Discapacidades para el Aprendizaje/genética , Masculino , Megalencefalia/genética , Proteínas del Tejido Nervioso/genética , Técnicas de Amplificación de Ácido Nucleico , Eliminación de Secuencia , Hermanos , SíndromeRESUMEN
Interphase heterogenous chromosomes spatially close to each other are predominantly located near the center of nuclei and are prone to incur translocations. We screened a t(8;21) (q22;q22) acute myeloid leukemia-M2 patient during three phases (post-chemotherapy, remittent stage, and relapse) and a donor of normal karyotype as control by two-(2D) and three-dimensional (3D)-fluorescence in situ hybridization (FISH). Our classification of nuclei (normal, transitional, and malignant nuclei) by 3D-FISH analyses may provide a more precise prognosis than 2D-FISH results, especially for remittent stage sample in our study, in which 2D-FISH findings showed normal results, whereas 3D-FISH results showed extreme abnormalities (normal nuclei 27%, transitional nuclei 36%, malignant nuclei 37%). The relative radial positions (d/R) of chromosomes 8 were similar to d/R of chromosomes 21 for the relapse sample. We classified heterogenous chromosome pairs into close pairs and normal pairs based on their relative distances (d'/(2R)). The centers of close pairs were more internal than normal pairs in nuclei in all samples, and the d/R values of a given-type pairwise heterogenous chromosomes were similar among four samples. Our data demonstrate that the classification of nuclei based on spatial organization of chromosomes by 3D-FISH is reasonable and essential for evaluating acute myeloid leukemia prognosis.
Asunto(s)
Núcleo Celular/ultraestructura , Cromosomas Humanos Par 21/ultraestructura , Cromosomas Humanos Par 8/ultraestructura , Inmunofenotipificación/métodos , Hibridación Fluorescente in Situ/métodos , Interfase , Leucemia Mieloide Aguda/genética , Translocación Genética , Células de la Médula Ósea/ultraestructura , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , PronósticoRESUMEN
PURPOSE: Breast angiosarcomas are rare vascular malignancies that arise secondary to irradiation or de novo as primary tumours. The aim of this study is to know whether c-myc amplification can reliably discriminate these two entities. MATERIEL AND METHODS: Forty-seven patients treated for breast angiosarcomas were studied. Thirty-two patients were diagnosed with postradiation angiosarcomas after breast cancer treatment and 15 patients with primary angiosarcomas. Interphase fluorescence in situ hybridization (FISH) was performed by hybridization of probes covering C-MYC (chromosome 8q24.21) and CEP8 on tissue sections. RESULTS: Amplification (5- to 20-fold) of the c-myc oncogene was found in all breast radiation-induced angiosarcomas (32 tumours) but in none of the 15 primary angiosarcomas except one (7%). CONCLUSION: This study reinforces that there are true pathogenetic differences between the two types of breast angiosarcomas which are morphologically indistinguishable. These data point the pathways preferentially involved in the pathogenesis of post radiation angiosarcomas of the breast and may provide the basis for an additional targeted therapy.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Amplificación de Genes , Genes myc , Hemangiosarcoma/diagnóstico , Neoplasias Inducidas por Radiación/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Teleterapia por Radioisótopo/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/radioterapia , Carcinoma Ductal de Mama/cirugía , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/ultraestructura , Terapia Combinada , ADN de Neoplasias/genética , Diagnóstico Diferencial , Femenino , Hemangiosarcoma/química , Hemangiosarcoma/genética , Humanos , Hibridación Fluorescente in Situ , Interfase , Escisión del Ganglio Linfático , Mastectomía , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/química , Neoplasias Inducidas por Radiación/genética , Neoplasias Primarias Secundarias/química , Neoplasias Primarias Secundarias/genéticaRESUMEN
The Wolf-Hirschhorn syndrome (WHS) encompasses deletions at the distal part of the short arm of one chromosome 4 (4p16 region). Clinical signs frequently include a typical facial appearance, mental retardation, intrauterine and postnatal growth retardation, hypotonia with decreased muscle bulk and seizures besides congenital heart malformations, midline defects, urinary tract malformations and brain, hearing and ophthalmologic malformations. Pathogenesis of WHS is multigenic and many factors are involved in prediction of prognosis such as extent of deletion, the occurrence of severe chromosome anomalies, the severe of seizures, the existence of serious internal, mainly cardiac, abnormalities and the degree of mental retardation. The phenotype of adult with WHS is in general similar to that of childhood being facial dysmorphism, growth retardation and mental retardation the rule in both adults and children. Avoid long-term complications and provide rehabilitation programs and genetic counseling may be essential in these patients.
Asunto(s)
Síndrome de Wolf-Hirschhorn/patología , Adolescente , Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 4/ultraestructura , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/ultraestructura , Ventrículo Derecho con Doble Salida/genética , Epilepsia Generalizada/genética , Facies , Femenino , Hallux Valgus/genética , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Cifosis/genética , Masculino , Fenotipo , Translocación Genética , Síndrome de Wolf-Hirschhorn/genéticaRESUMEN
Branchio-oto-renal (BOR) syndrome is an autosomal dominantly inherited developmental disorder, which is characterized by anomalies of the ears, the branchial arches and the kidneys. It is caused by mutations in the genes EYA1,SIX1 and SIX5. Genomic rearrangements of chromosome 8 affecting the EYA1 gene have also been described. Owing to this fact, methods for the identification of abnormal copy numbers such as multiplex ligation-dependent probe amplification (MLPA) have been introduced as routine laboratory techniques for molecular diagnostics of BOR syndrome. The advantages of these techniques are clear compared to standard cytogenetic and array approaches as well as Southern blot. MLPA detects deletions or duplications of a part or the entire gene of interest, but not balanced structural aberrations such as inversions and translocations. Consequently, disruption of a gene by a genomic rearrangement may escape detection by a molecular genetic analysis, although this gene interruption results in haploinsufficiency and, therefore, causes the disease. In a patient with clinical features of BOR syndrome, such as hearing loss, preauricular fistulas and facial dysmorphisms, but no renal anomalies, neither sequencing of the 3 genes linked to BOR syndrome nor array comparative genomic hybridization and MLPA were able to uncover a causative mutation. By routine cytogenetic analysis, we finally identified a pericentric inversion of chromosome 8 in the affected female. High-resolution multicolor banding confirmed the chromosome 8 inversion and narrowed down the karyotype to 46,XX,inv(8)(p22q13). By applying fluorescence in situ hybridization, we narrowed down both breakpoints on chromosome 8 and found the EYA1 gene in q13.3 to be directly disrupted. We conclude that standard karyotyping should not be neglected in the genetic diagnostics of BOR syndrome or other Mendelian disorders, particularly when molecular testing failed to detect any causative alteration in patients with a convincing phenotype.
Asunto(s)
Síndrome Branquio Oto Renal/genética , Inversión Cromosómica , Cromosomas Humanos Par 8/ultraestructura , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatasas/genética , Adulto , Síndrome Branquio Oto Renal/patología , Puntos de Rotura del Cromosoma , Cromosomas Humanos Par 8/genética , Hibridación Genómica Comparativa , Femenino , Pérdida Auditiva Sensorineural/etiología , Proteínas de Homeodominio/genética , Humanos , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular/química , Reacción en Cadena de la Polimerasa Multiplex , Proteínas Nucleares/química , Fenotipo , Proteínas Tirosina Fosfatasas/químicaRESUMEN
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a disease of older adults. Pediatric CLL/SLL is vanishingly rare in the literature. We present a case of CLL/SLL diagnosed in a 17-year-old male. The pathologic findings of this case were those of classic CLL/SLL with an ATM deletion, a characteristic genetic abnormality in CLL/SLL. Management guidelines for CLL/SLL are tailored to older adults making determination of the optimal therapy for this patient a unique challenge.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Adolescente , Factores de Edad , Proteínas de la Ataxia Telangiectasia Mutada/genética , Biomarcadores de Tumor , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/ultraestructura , Diagnóstico por Imagen , Dosificación de Gen , Genes myc , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/genética , Ganglios Linfáticos/patología , Masculino , Eliminación de SecuenciaAsunto(s)
Cromosomas Humanos Par 8/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Proteínas de Fusión Oncogénica/fisiología , Translocación Genética , Adulto , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 9/genética , Eritropoyesis , Células Madre Hematopoyéticas/patología , Humanos , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Células Neoplásicas Circulantes , Células Madre Neoplásicas/patología , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/análisis , Factor de Transcripción STAT5/análisisRESUMEN
The translocation t(8;9)(p22;p24) is a rare event that results in the fusion of JAK2 to PCM1 and thus leads to the activation of the Janus Kinase 2. In 2008, the WHO introduced a new entity called "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1", which are characterized by the formation of a fusion gene encoding an aberrant tyrosine kinase. These disorders share characteristics with myeloproliferative neoplasms and typically show an eosinophilia. We here now report on 6 new cases with PCM1-JAK2 fusion. These patients show characteristics with respect to epidemiology, clinical presentation, and genetic changes that are very similar to patients with rearrangements of PDGFRA, PDGFRB, or FGFR1. Our data suggests the integration of cases with JAK2-PCM1 fusion in the respective WHO category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1.