RESUMEN
Anaplastic lymphoma kinase (ALK) and MYC are oncogenes often dysregulated in pediatric lymphomas. NPM-ALK/t(2;5)(p23;q35) is a genetic hallmark of ALK anaplastic large cell lymphoma (ALCL). MYC gene translocations are frequently detected in high-grade B-cell lymphomas. ALKALCL cases with concurrent MYC translocation are exceedingly rare and are more aggressive and chemoresistent compared with other ALKALCL. We report a patient who presented with ALKALCL possessing coexistent MYC rearrangement, massive tumor dissemination, and early widespread relapse. This case underscores the importance of recognition of close correlation between dual ALK and MYC rearrangements and the characteristic clinical features in this unusual ALCL variant.
Asunto(s)
Reordenamiento Génico , Linfoma Anaplásico de Células Grandes/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico , Niño , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/fisiopatología , Masculino , Proteínas de Fusión Oncogénica/genética , Translocación GenéticaRESUMEN
Cystathionine beta-synthase (CBS) catalyzes the condensation of homocysteine (Hcy) and serine to cystathionine, which is then hydrolyzed to cysteine by cystathionine gamma-lyase. Inactivation of CBS results in CBS-deficient homocystinuria more commonly referred to as classical homocystinuria, which, if untreated, results in mental retardation, thromboembolic complications, and a range of connective tissue disorders. The molecular mechanisms that underlie the pathology of this disease are poorly understood. We report here the generation of a new mouse model of classical homocystinuria in which the mouse cbs gene is inactivated and that exhibits low-level expression of the human CBS transgene under the control of the human CBS promoter. This mouse model, designated "human only" (HO), exhibits severe elevations in both plasma and tissue levels of Hcy, methionine, S-adenosylmethionine, and S-adenosylhomocysteine and a concomitant decrease in plasma and hepatic levels of cysteine. HO mice exhibit mild hepatopathy but, in contrast to previous models of classical homocystinuria, do not incur hepatic steatosis, fibrosis, or neonatal death with approximately 90% of HO mice living for at least 6months. Tail bleeding determinations indicate that HO mice are in a hypercoagulative state that is significantly ameliorated by betaine treatment in a manner that recapitulates the disease as it occurs in humans. Our findings indicate that this mouse model will be a valuable tool in the study of pathogenesis in classical homocystinuria and the rational design of novel treatments.
Asunto(s)
Betaína/uso terapéutico , Cistationina betasintasa/deficiencia , Homocistinuria/genética , Animales , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea/etiología , Cistationina/sangre , Modelos Animales de Enfermedad , Hígado Graso/patología , Fibrosis , Homocistinuria/tratamiento farmacológico , Homocistinuria/patología , Ratones , Ratones TransgénicosRESUMEN
Given that gene duplication is a major driving force of evolutionary change and the key mechanism underlying the emergence of new genes and biological processes, this study sought to use a novel genome-wide approach to identify genes that have undergone lineage-specific duplications or contractions among several hominoid lineages. Interspecies cDNA array-based comparative genomic hybridization was used to individually compare copy number variation for 39,711 cDNAs, representing 29,619 human genes, across five hominoid species, including human. We identified 1,005 genes, either as isolated genes or in clusters positionally biased toward rearrangement-prone genomic regions, that produced relative hybridization signals unique to one or more of the hominoid lineages. Measured as a function of the evolutionary age of each lineage, genes showing copy number expansions were most pronounced in human (134) and include a number of genes thought to be involved in the structure and function of the brain. This work represents, to our knowledge, the first genome-wide gene-based survey of gene duplication across hominoid species. The genes identified here likely represent a significant majority of the major gene copy number changes that have occurred over the past 15 million years of human and great ape evolution and are likely to underlie some of the key phenotypic characteristics that distinguish these species.
Asunto(s)
Evolución Molecular , Duplicación de Gen , Animales , Evolución Biológica , Cromosomas Artificiales Bacterianos , Clonación Molecular , Análisis por Conglomerados , ADN Complementario/metabolismo , Factor 7 de Crecimiento de Fibroblastos/metabolismo , Variación Genética , Genoma , Hominidae , Humanos , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular , Modelos Genéticos , Datos de Secuencia Molecular , Familia de Multigenes , Hibridación de Ácido Nucleico , Pan troglodytes , Pongo pygmaeus , Proteínas/metabolismo , Secuencias Repetitivas de Ácidos Nucleicos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Especificidad de la EspecieRESUMEN
Most adult glioblastoma multiformes (GBMs) present in patients 45-70 years old; tumors occurring at the extremes of the adult age spectrum are uncommon, and seldom studied. We hypothesized that young-adult GBMs would differ from elderly-adult and from pediatric GBMs. Cases were identified from years 1997 to 2005. Demographic and histological features, MIB-1 and TP53 immunohistochemical findings and epidermal growth factor receptor (EGFR) amplification status by fluorescence in situ hybridization were compiled and correlated with survival. Twenty-eight (74%) of our 38 young-adult GBM patients had primary de novo tumors, two of which occurred in patients with cancer syndromes. Two additional GBMs were radiation-induced and eight (21%) were secondary GBMs. Seven patients were identified as long-term (>3 years) survivors. Six of 38 cases manifested unusual morphological features, including three epithelioid GBMs, one rhabdoid GBM, one gliosarcoma and one small cell GBM containing abundant, refractile, eosinophilic inclusions. MIB-1 index emerged as the most important prognosticator of survival (P < 0.005). Although there was a trend between extent of necrosis, TP53 immunohistochemical expression, and EGFR amplification status and survival, none reached statistical significance. GBMs in young adults are a more inhomogeneous tumor group than GBMs occurring in older adult patients and show features that overlap with both pediatric and adult GBMs.
Asunto(s)
Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Glioblastoma/mortalidad , Glioblastoma/patología , Adolescente , Adulto , Neoplasias Encefálicas/etiología , Receptores ErbB/metabolismo , Femenino , Glioblastoma/etiología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Antígeno Ki-67/metabolismo , Masculino , Índice Mitótico , Neoplasias Inducidas por Radiación , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/patología , Pronóstico , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disease characterized by multiple recurring clonal cytogenetic anomalies and is the most common leukemia in adults. Chromosomal abnormalities associated with CLL include trisomy 12 and IGH;BCL3 rearrangement [t(14;19)(q32;q13)] that juxtaposes a proto-oncogenic gene BCL3 and an immunoglobulin heavy chain, a translocation that may be associated with shorter survival. In addition to the IGH;BCL3 rearrangement, other translocations involving 14q32 locus are involved in various lymphoproliferative pathologies pointing toward the significance of IGH locus in oncogenic progression. Significantly, in the majority of B-cell neoplasms that carry an IGH;BCL3 rearrangement, it is a sole translocation involving an IGH locus. CASE PRESENTATION: We report a patient who, in addition to trisomy 12, carried a rare double-hit translocation characterized by the IGH;BCL3 translocation and an additional clonal IGH;BCL2 translocation involving IGH and another proto-oncogene BCL2, t(14;18)(q32;q21), commonly found in follicular lymphoma. Further single nucleotide polymorphism (SNP) array-based analysis detected a duplication of the 58.8 kb region at 19q13.32 adjacent to the BCL3 translocation junction on chromosome 19q13. Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum. CONCLUSIONS: Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3. Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.
RESUMEN
BCL2 and MYC are oncogenes often deregulated in lymphomas. Concurrent IGH-BCL2 and MYC translocations result in a highly aggressive behavior of these tumors. Both primary breast lymphoma and lymphoma with concurrent BCL2-IGH and MYC translocations are rare and are primarily seen in adult patients. As a result of limited clinician experience and the condition's rarity, it poses a great challenge to pediatric pathologists and oncologists in terms of making an accurate diagnosis and choosing better treatment regimens. In this article, we report a case of an adolescent patient who presented with high-grade breast lymphoma with concurrent BCL2-IGH and MYC-IGL translocations, and we review the clinical, pathological, and genetic features; management strategies; and outcomes associated with this unusual neoplasm.
Asunto(s)
Neoplasias de la Mama/patología , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Genes de las Cadenas Ligeras de las Inmunoglobulinas/genética , Linfoma de Células B/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Cariotipo Anormal , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Terapia Combinada , ADN de Neoplasias/análisis , Resultado Fatal , Femenino , Regulación Neoplásica de la Expresión Génica , Reordenamiento Génico de Cadena Pesada de Linfocito B/genética , Humanos , Linfoma de Células B/genética , Linfoma de Células B/terapia , Translocación Genética , Adulto JovenRESUMEN
Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder (PTLD) is a well-recognized complication of immunosuppression in transplant patients and has broad clinical manifestations and pathologic features ranging from reactive lymphoid proliferation to malignant lymphoma. The category of Hodgkin lymphoma and Hodgkin lymphomalike PTLD is an uncommon variant of PTLD. Development of Hodgkin lymphoma subsequent to other subtypes of PTLD in the same patient is even more unusual, especially in pediatric patients. In this report, we describe a pediatric case of Epstein-Barr virus-associated posttransplant Hodgkin lymphoma developing several years after the patient was diagnosed with polymorphic PTLD and review the literature of the previously reported cases in children to further help characterize the clinical features, histopathologic appearances, biology, and treatment strategies of this uncommon entity.
Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología , Enfermedad de Hodgkin/inmunología , Trasplante de Hígado/efectos adversos , Trastornos Linfoproliferativos/inmunología , Tonsila Faríngea/patología , Adulto , Atresia Biliar/cirugía , Niño , Infecciones por Virus de Epstein-Barr/complicaciones , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/virología , Humanos , Huésped Inmunocomprometido , Inmunohistoquímica , Terapia de Inmunosupresión/efectos adversos , Hibridación Fluorescente in Situ , Lactante , Ganglios Linfáticos/patología , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/virología , Masculino , Tonsila Palatina/patología , Reacción en Cadena de la Polimerasa , Lesiones Precancerosas/complicaciones , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/virología , ARN Viral/análisis , Células de Reed-Sternberg/patologíaRESUMEN
Extreme gene duplication is a major source of evolutionary novelty. A genome-wide survey of gene copy number variation among human and great ape lineages revealed that the most striking human lineage-specific amplification was due to an unknown gene, MGC8902, which is predicted to encode multiple copies of a protein domain of unknown function (DUF1220). Sequences encoding these domains are virtually all primate-specific, show signs of positive selection, and are increasingly amplified generally as a function of a species' evolutionary proximity to humans, where the greatest number of copies (212) is found. DUF1220 domains are highly expressed in brain regions associated with higher cognitive function, and in brain show neuron-specific expression preferentially in cell bodies and dendrites.