Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Neumonía en Organización Criptogénica/etiología , Síndromes Mielodisplásicos/complicaciones , Anciano , Neumonía en Organización Criptogénica/diagnóstico por imagen , Neumonía en Organización Criptogénica/tratamiento farmacológico , Neumonía en Organización Criptogénica/genética , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Prednisolona/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: Triphalangeal thumb-polysyndactyly syndrome (TPT-PS) is a rare well-defined autosomal dominant disorder characterized by long thumbs with three phalanges combined with pre- and postaxial polydactyly/syndactyly of limbs. By now, the syndrome has been reported in several large families from different ethnic backgrounds, with a high degree of inter- and intrafamilial variability. The genome locus responsible for TPT-PS has been mapped to the 7q36.3 region harboring a long-range sonic hedgehog (SHH) regulatory sequence (ZRS). Both single-nucleotide variants and complete duplications of ZRS were shown to cause TPT-PS and similar limb phenotypes. TPT-PS usually forms as isolated limb pathology not associated with additional malformations, in particular, with cardiovascular abnormalities. CASE PRESENTATION: Here we report on a rare Russian neonatal case of TPT-PS combined with severe congenital heart disease, namely double outlet right ventricle, and microphthalmia with optic disc coloboma. Pedigree analysis revealed TPT-PS of various expressivity in 10 family members throughout five generations, while the cardiac defect and the eye pathology were detected only in the proband. To extend the knowledge on genotype-phenotype spectrum of TPT-PS, the careful clinical and genomic analysis of the family was performed. High-resolution array-based comparative genomic hybridization (array-CGH) revealed a ~ 300 kb microduplication of 7q36.3 locus (arr[GRCh37] 7q36.3(156385810_156684811) × 3) that co-segregated with TPT-PS in the proband and her mother. The duplication encompassed three genes including LMBR1, the intron 5 of which is known to harbor ZRS. Based on whole-exome sequencing data, no additional pathogenic mutations or variants of uncertain clinical significance were found in morbid cardiac genes or genes associated with a microphthalmia/anophthalmia/coloboma spectrum of ocular malformations. CONCLUSIONS: The results support the previous data, indicating that complete ZRS duplication underlies TPT-PS, and suggest a broader phenotypic impact of the 7q36.3 microduplication. Potential involvement of the 7q36.3 microduplication in the patient's cardiac and eye malformations is discussed. However, the contribution of some additional genetic/epigenetic factors to the complex patient`s phenotype cannot be excluded entirely. Further comprehensive functional studies are needed to prove the possible involvement of the 7q36.3 locus in congenital heart disease and eye pathology.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 7/genética , Coloboma/genética , Anomalías Congénitas/genética , Ventrículo Derecho con Doble Salida/genética , Duplicación de Gen , Disostosis Mandibulofacial/genética , Microftalmía/genética , Disco Óptico/anomalías , Adulto , Cromosomas Humanos Par 7/ultraestructura , Hibridación Genómica Comparativa , Femenino , Humanos , Lactante , Masculino , Proteínas de la Membrana/genética , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Síndrome , Arterias Umbilicales/anomalíasRESUMEN
Copy number variations (CNVs) play a key role in the pathogenesis of several diseases, including a wide range of neurodevelopmental disorders. Here, we describe the detection of three CNVs simultaneously in a female patient with evidence of severe myoclonic epilepsy, microcephaly, hypertelorism, dimorphisms as well as severe psychomotor delay and intellectual disability. Array-CGH analysis revealed a â¼240 kb microdeletion at the 7q35 inherited from her father, a â¼538 kb microduplication at the 15q13.3 region and a â¼178 kb microduplication at Xp22.33 region, both transmitted from her mother. The microdeletion in 7q35 was included within an intragenic region of the contactin associated protein-like 2 (CNTNAP2) gene, whereas the microduplications at 15q13.3 and Xp22.33 involved the cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and the cytokine receptor-like factor 2 (CRLF2) genes, respectively. Here, we describe a female patient harbouring three CNVs whose additive contribution could be responsible for her clinical phenotypes.
Asunto(s)
Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos X/genética , Epilepsias Mioclónicas/genética , Microcefalia/genética , Trastornos del Neurodesarrollo/genética , Adulto , Cromosomas Humanos Par 15/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Cromosomas Humanos X/ultraestructura , Consanguinidad , Variaciones en el Número de Copia de ADN , Femenino , Duplicación de Gen , Estudios de Asociación Genética , Humanos , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Linaje , Receptores de Citocinas/genética , Eliminación de Secuencia , Análisis de Matrices Tisulares , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
GLI family zinc finger proteins are transcriptional effectors of the sonic hedgehog signaling pathway. GLI regulates gene expression and repression at various phases of embryonic morphogenesis. In humans, 4 GLI genes are known, and GLI2 (2q14.2) and GLI3 (7p14.1) mutations cause different syndromes. Here, we present 2 distinctive cases with a chromosomal microdeletion in one of these genes. Patient 1 is a 14-year-old girl with Culler-Jones syndrome. She manifested short stature, cleft palate, and mild intellectual/social disability caused by a 6.6-Mb deletion of 2q14.1q14.3. Patient 2 is a 2-year-old girl with Greig cephalopolysyndactyly contiguous gene deletion syndrome. She manifested macrocephaly, preaxial polysyndactyly, psychomotor developmental delay, cerebral cavernous malformations, and glucose intolerance due to a 6.2-Mb deletion of 7p14.1p12.3 which included GLI3, GCK, and CCM2. Each patient manifests a different phenotype which is associated with different functions of each GLI gene and different effects of the chromosomal contiguous gene deletion. We summarize the phenotypic extent of GLI2/3 syndromes in the literature and determine that these 2 syndromes manifest opposite features to a certain extent, such as midface hypoplasia or macrocephaly, and anterior or posterior side of polydactyly. We propose a GLIA/R balance model that may explain these findings.
Asunto(s)
Anomalías Múltiples/genética , Acrocefalosindactilia/genética , Cromosomas Humanos Par 2/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Proteínas del Tejido Nervioso/deficiencia , Proteínas Nucleares/deficiencia , Proteína Gli2 con Dedos de Zinc/deficiencia , Proteína Gli3 con Dedos de Zinc/deficiencia , Adolescente , Preescolar , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 7/genética , Fisura del Paladar/genética , Enanismo/genética , Femenino , Intolerancia a la Glucosa/genética , Proteínas Hedgehog/fisiología , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Humanos , Discapacidad Intelectual/genética , Cariotipificación , Modelos Biológicos , Morfogénesis/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Eliminación de Secuencia , Transducción de Señal/genética , Síndrome , Proteína Gli2 con Dedos de Zinc/genética , Proteína Gli2 con Dedos de Zinc/fisiología , Proteína Gli3 con Dedos de Zinc/genética , Proteína Gli3 con Dedos de Zinc/fisiologíaAsunto(s)
Transformación Celular Neoplásica/genética , Deleción Cromosómica , Cromosomas Humanos Par 7/ultraestructura , Eliminación de Gen , Leucemia Mieloide Aguda/etiología , Linfoma Folicular/terapia , Linfoma de Células del Manto/terapia , Síndromes Mielodisplásicos/etiología , Neoplasias Primarias Secundarias/etiología , Trasplante de Células Madre de Sangre Periférica , Cromosomas en Anillo , Aloinjertos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Biomarcadores de Tumor , Médula Ósea/patología , Cromosomas Humanos Par 7/genética , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Donadores Vivos , Linfoma Folicular/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Neoplasias Primarias Secundarias/patología , Proteínas Proto-Oncogénicas c-ets/deficiencia , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/deficiencia , Proteínas Represoras/genética , Rituximab , Quimera por Trasplante/genética , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Proteína ETS de Variante de Translocación 6Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Leucemia Mieloide Aguda/genética , Translocación Genética , Trisomía , Anciano , Bandeo Cromosómico , Pintura Cromosómica , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 7/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Dosificación de Gen , N-Metiltransferasa de Histona-Lisina , Humanos , Masculino , Proteína de la Leucemia Mieloide-Linfoide/genéticaRESUMEN
The combined 1p-/19q- deletions in oligodendrogliomas originate from translocation between both chromosomes. In the few cases of oligoastrocytomas and glioblastomas with an oligodendroglioma component (GBMO) where only 1p deletion was described, the origin remains unknown. We report the first case of GBMO, in which a single 1p deletion was detected and was linked to a translocation between chromosomes 1 and 7. Fresh surgical specimens were collected during surgery and the samples were used for cell culture, touch preparation smear slides (TP slides) and DNA extraction. Peripheral venous blood was also collected from the patient. G-banding using Trypsin and stained with Giemsa (GTG) banding and karyotyping were performed and 1p-/19q-, TP53, PTEN and c-MYC were analyzed by fluorescent in situ hybridization (FISH). Multicolor FISH (mFISH) and microsatellites analyses were also performed to complete the investigation. Three-dimensional quantitative FISH (3D-QFISH) of telomeres was performed on nuclei from TP slides and analyzed using TeloView(TM) to determine whether the 3D telomere profile as an assessment of telomere dysfunction and a characterization of genomic instability could predict the disease aggressiveness. An unbalanced chromosomal translocation was found in all metaphases and confirmed by mFISH. The karyotype of the case is: 50â¼99,XXX, +der(1;7)(q10;p10),inc[47] The derivative chromosome was found in all 47 analyzed cells, but the number of derivatives varied from one to four. There was neither imbalance in copy number for genes TP53 and PTEN, nor amplification of c-MYC gene. We did not find loss of heterozygosity with analysis of microsatellite markers for chromosomes 1p and 19q in tumor cells. The 3D-telomere profile predicted a very poor prognostic and short-term survival of the patient and highlights the potential clinical power of telomere signatures as a solid biomarker of GBMO. Furthermore, this translocation between chromosomes 1 and 7 led to a singular 1p deletion in this GBMO and may generate the 1p and 7q deletions.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Deleción Cromosómica , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 7/genética , Glioblastoma/genética , Glioblastoma/patología , Oligodendroglioma/genética , Oligodendroglioma/patología , Adulto , Neoplasias Encefálicas/cirugía , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 10/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Citogenética , Femenino , Glioblastoma/cirugía , Humanos , Inmunohistoquímica , Oligodendroglioma/cirugía , Telómero/genética , Telómero/ultraestructuraAsunto(s)
Crisis Blástica/genética , Cromosomas Humanos Par 12/ultraestructura , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Translocación Genética , Adulto , Médula Ósea/patología , Bandeo Cromosómico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 9/genética , Errores Diagnósticos , Humanos , Hibridación Fluorescente in Situ , Ganglios Linfáticos/patología , Masculino , Trastornos Mieloproliferativos/clasificación , Trastornos Mieloproliferativos/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMEN
OBJECTIVE: To assess the value of the study of chromosomal alterations by fluorescent in situ hybridization in a series of patients diagnosed of urothelial carcinoma and a minimum follow up of twenty four months, as well as evaluate its putative predictive potential. MATERIAL AND METHODS: The overall series includes 338 samples from 98 patients with 84 episodes of urothelial carcinoma. A subgroup of 24 patients who had at least one recurrence during the follow up was used to evaluate the predictive potential of the test. Three categories were considered (positive coherent episode, negative coherent episode, and incoherent episode) depending on the relationship between the fluorescent in situ hybridization result in the concomitant study of the new episode and those of the preceding samples. RESULTS: Fluorescent in situ hybridization showed higher sensitivity regardless of grade, negative predictive value and accuracy, while specificity and positive predictive value were superior with conventional cytology. In the recurrence, series 19/29 episodes were coherent, 11/19 were positive coherent with urothelial carcinoma all high grade and 8/19 negative coherent, most low grade. CONCLUSIONS: Fluorescent in situ hybridization test shows good sensitivity during a follow up of twenty four months and is able to predict recurrence, especially in cases of high grade. Our data demonstrate the existence of urothelial carcinomas without detectable chromosomal abnormalities by currently available methodology. The results support a multidisciplinary follow up combining fluorescent in situ hybridization, cytology and cystoscopy.
Asunto(s)
Carcinoma de Células Transicionales/genética , Aberraciones Cromosómicas , Hibridación Fluorescente in Situ , Recurrencia Local de Neoplasia/genética , Neoplasias de la Vejiga Urinaria/genética , Algoritmos , Aneuploidia , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/epidemiología , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/terapia , Cromosomas Humanos Par 17/ultraestructura , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/ultraestructura , Cistoscopía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Prueba de Papanicolaou , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Orina/citologíaAsunto(s)
Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 7/genética , Mieloma Múltiple/genética , Polimorfismo de Nucleótido Simple , Bancos de Muestras Biológicas , Mapeo Cromosómico , Cromosomas Humanos Par 2/ultraestructura , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Femenino , Genes myc , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Alemania/epidemiología , Humanos , Masculino , Mieloma Múltiple/epidemiología , Riesgo , Reino Unido/epidemiologíaRESUMEN
Using high-resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Deletion or uniparental disomy of chromosome 7q were detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%) mature B-cell lymphomas (P < 0·00001). The presence of unmutated IGHV, genomic complexity, 17p13-TP53 deletion and 8q-MYC gain, but not 7q deletion, correlated with shorter overall survival of SMZL patients. Mapping studies narrowed down a commonly deleted region of 2·7 Mb in 7q32.1-q32.2 spanning a region between the SND1 and COPG2 genes. High-throughput sequencing analysis of the 7q32-deleted segment did not identify biallelic deletions/insertions or clear pathogenic gene mutations, but detected six nucleotide changes in IRF5 (n = 2), TMEM209 (n = 2), CALU (n = 1) and ZC3HC1 (n = 1) not found in healthy individuals. Comparative expression analysis found a fourfold down-regulation of IRF5 gene in lymphomas with 7q32 deletion versus non-deleted tumours (P = 0·032). Ectopic expression of IRF5 in marginal-zone lymphoma cells decreased proliferation and increased apoptosis in vitro, and impaired lymphoma development in vivo. These results show that cryptic deletions, insertions and/or point mutations inactivating genes within 7q32 are not common in SMZL, and suggest that IRF5 may be a haploinsufficient tumour suppressor in this lymphoma entity.
Asunto(s)
Cromosomas Humanos Par 7/genética , Genes Supresores de Tumor , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Factores Reguladores del Interferón/genética , Linfoma de Células B de la Zona Marginal/genética , Proteínas de Neoplasias/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Eliminación de Secuencia , Neoplasias del Bazo/genética , Animales , Apoptosis/genética , División Celular/efectos de los fármacos , Línea Celular Tumoral/trasplante , Cromosomas Humanos Par 7/ultraestructura , Hibridación Genómica Comparativa , Regulación Neoplásica de la Expresión Génica , Genes de Inmunoglobulinas , Humanos , Factores Reguladores del Interferón/biosíntesis , Factores Reguladores del Interferón/deficiencia , Factores Reguladores del Interferón/fisiología , Estimación de Kaplan-Meier , Linfoma de Células B de la Zona Marginal/mortalidad , Linfoma de Células B de la Zona Marginal/patología , Ratones , Ratones Noqueados , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/fisiología , Mutación Puntual , Reacción en Cadena en Tiempo Real de la Polimerasa , Neoplasias del Bazo/mortalidad , Neoplasias del Bazo/patología , Translocación GenéticaRESUMEN
Gilles de la Tourette syndrome is a complex neuropsychiatric disorder with a strong genetic basis. We identified a male patient with Tourette syndrome-like tics and an apparently balanced de novo translocation [46,XY,t(2;7)(p24.2;q31)]. Further analysis using array comparative genomic hybridisation (CGH) revealed a cryptic deletion at 7q31.1-7q31.2. Breakpoints disrupting this region have been reported in one isolated and one familial case of Tourette syndrome. In our case, IMMP2L, a gene coding for a human homologue of the yeast inner mitochondrial membrane peptidase subunit 2, was disrupted by the breakpoint on 7q31.1, with deletion of exons 1-3 of the gene. The IMMP2L gene has previously been proposed as a candidate gene for Tourette syndrome, and our case provides further evidence of its possible role in the pathogenesis. The deleted region (7q31.1-7q31.2) of 7.2 Mb of genomic DNA also encompasses numerous genes, including FOXP2, associated with verbal dyspraxia, and the CFTR gene.
Asunto(s)
Puntos de Rotura del Cromosoma , Cromosomas Humanos Par 7/genética , ADN/análisis , Endopeptidasas/genética , Tics/genética , Síndrome de Tourette , Apraxias/genética , Apraxias/fisiopatología , Cromosomas Humanos Par 7/ultraestructura , Hibridación Genómica Comparativa , Regulador de Conductancia de Transmembrana de Fibrosis Quística/deficiencia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Endopeptidasas/metabolismo , Exones , Factores de Transcripción Forkhead/deficiencia , Factores de Transcripción Forkhead/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Eliminación de Secuencia , Tics/fisiopatología , Síndrome de Tourette/genética , Síndrome de Tourette/fisiopatología , Translocación GenéticaRESUMEN
Fanconi Anemia (FA) is an inherited bone marrow failure syndrome characterized by congenital abnormalities, progressive marrow failure and predisposition to myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. The most common acquired chromosomal aberrations in FA patients are trisomy of 1q and monosomy of chromosome 7; the latter is known to be associated with poor prognosis. A few reports also suggest that gains of 3q are associated with progression to MDS-AML and overall poor prognosis. It is not uncommon for patients with Fanconi anemia to have easily detectable (oligoclonal) chromosomal alterations in their still normal (nonmalignant) marrow, which makes it even more challenging to determine the import of such alterations. We conducted a retrospective longitudinal analysis of fluorescent in situ hybridization (FISH) analysis for gains in 1q and 3q and for monosomy 7 and 7q deletions on 212 bone marrow samples from 77 children with FA treated at our institution between 1987 and 2007. Given the baseline increased chromosomal instability and defective DNA repair in patients with FA, which leads to unbalanced chromosomal aberrations such as deletions, insertions, and translocations, for the purpose of this analysis an abnormal clone was defined as ≥10% abnormal cells. Chromosome 3 and 7 aberrations were associated with increased risk of developing MDS-AML (P = 0.019 and P < 0.001 respectively), although the significance of chromosome 3 aberrations disappeared when different observation times were accounted for. Gain of 1q alone did not predict development of MDS-AML. In conclusion, children with FA should be followed closely with FISH analyses, because some of the clonal chromosomal abnormalities may be early indicators of progression toward MDS-AML and thus also of the need for hematopoietic stem cell transplantation.
Asunto(s)
Deleción Cromosómica , Mapeo Cromosómico , Anemia de Fanconi/complicaciones , Anemia de Fanconi/genética , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genética , Adolescente , Adulto , Niño , Preescolar , Cromosomas/ultraestructura , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , RiesgoRESUMEN
Despite growing evidence that epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation analysis is the most reliable predictor of the lung carcinoma response to EGFR-targeted therapies, there is still discussion about the role of EGFR fluorescence in situ hybridization (FISH). Studies focusing on EGFR FISH as a predictor of response to EGFR-targeted therapies mostly focused on the relationship between EGFR FISH and EGFR mutations. The incidence of KRAS and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in EGFR-amplified or EGFR FISH-positive lung adenocarcinomas remains unknown. The aim of this study was to prospectively characterize the incidence of KRAS and BRAF mutations in EGFR FISH-positive surgically treated lung adenocarcinomas. Of 386 primary lung adenocarcinomas, 77 (20%) were EGFR FISH positive by University of Colorado criteria. The incidence of KRAS mutations in EGFR FISH-positive lung adenocarcinomas was 23% and was not significantly different from the incidence of KRAS mutations in EGFR FISH-negative subsets of adenocarcinoma (32%). A higher mean ratio between EGFR and chromosome 7 enumeration probe (EGFR/CEP7) was observed in EGFR-mutated tumors when compared to cases with KRAS mutation (13 versus 4.5, respectively). Our results showed significant number of EGFR FISH positive/amplified lung adenocarcinomas harboring KRAS mutation. It appears that an increase in EGFR/CEP7 ratio to cutoff point of 4.5 may distinguish between coexisting EGFR (FISH ratio of >5) or KRAS (FISH ratio of 2 to 5) mutations. Observations presented here indicate that the patient selection for EGFR-targeted therapies should include EGFR and KRAS mutational analysis, probably complemented by EGFR FISH studies.
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Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/ultraestructura , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Polirribosomas/genética , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
BACKGROUND: Stem cell expansion and differentiation is the foundation of emerging cell therapy technologies. The potential applications of human neural progenitor cells (hNPCs) are wide ranging, but a normal cytogenetic profile is important to avoid the risk of tumor formation in clinical trials. FDA approved clinical trials are being planned and conducted for hNPC transplantation into the brain or spinal cord for various neurodegenerative disorders. Although human embryonic stem cells (hESCs) are known to show recurrent chromosomal abnormalities involving 12 and 17, no studies have revealed chromosomal abnormalities in cultured hNPCs. Therefore, we investigated frequently occurring chromosomal abnormalities in 21 independent fetal-derived hNPC lines and the possible mechanisms triggering such aberrations. METHODS AND FINDINGS: While most hNPC lines were karyotypically normal, G-band karyotyping and fluorescent in situ hybridization (FISH) analyses revealed the emergence of trisomy 7 (hNPC(+7)) and trisomy 19 (hNPC(+19)), in 24% and 5% of the lines, respectively. Once detected, subsequent passaging revealed emerging dominance of trisomy hNPCs. DNA microarray and immunoblotting analyses demonstrate epidermal growth factor receptor (EGFR) overexpression in hNPC(+7) and hNPC(+19) cells. We observed greater levels of telomerase (hTERT), increased proliferation (Ki67), survival (TUNEL), and neurogenesis (beta(III)-tubulin) in hNPC(+7) and hNPC(+19), using respective immunocytochemical markers. However, the trisomy lines underwent replicative senescence after 50-60 population doublings and never showed neoplastic changes. Although hNPC(+7) and hNPC(+19) survived better after xenotransplantation into the rat striatum, they did not form malignant tumors. Finally, EGF deprivation triggered a selection of trisomy 7 cells in a diploid hNPC line. CONCLUSIONS: We report that hNPCs are susceptible to accumulation of chromosome 7 and 19 trisomy in long-term cell culture. These results suggest that micro-environmental cues are powerful factors in the selection of specific hNPC aneuploidies, with trisomy of chromosome 7 being the most common. Given that a number of stem cell based clinical trials are being conducted or planned in USA and a recent report in PLoS Medicine showing the dangers of grafting an inordinate number of cells, these data substantiate the need for careful cytogenetic evaluation of hNPCs (fetal or hESC-derived) before their use in clinical or basic science applications.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Cromosomas Humanos Par 19/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Neuronas/citología , Células Madre/citología , Trisomía , Encéfalo/embriología , Aberraciones Cromosómicas , Citogenética , Células Madre Embrionarias/citología , Receptores ErbB/metabolismo , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Análisis de Secuencia por Matrices de OligonucleótidosAsunto(s)
Azatioprina/efectos adversos , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Síndrome Hipereosinofílico/tratamiento farmacológico , Inmunosupresores/efectos adversos , Leucemia Eritroblástica Aguda/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azatioprina/administración & dosificación , Azatioprina/uso terapéutico , Médula Ósea/patología , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 7/genética , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Quimioterapia Combinada , Resultado Fatal , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Persona de Mediana Edad , Neutropenia/etiología , Choque Séptico/etiologíaRESUMEN
The high incidence of de novo chromosomal aberrations in a population of persons with autism suggests a causal relationship between certain chromosomal aberrations and the occurrence of isolated idiopathic autism. We report on the clinical and cytogenetic findings in a male patient with autism, no physical abnormalities and a de novo balanced (7;16)(p22.1;p16.2) translocation. G-banded chromosomes and fluorescent in situ hybridization (FISH) were used to examine the patient's karyotype as well as his parents'. FISH with specific RP11-BAC clones mapping near 7p22.1 and 16p11.2 was used to refine the location of the breakpoints. This is, in the best of our knowledge, the first report of an individual with autism and this specific chromosomal aberration.
Asunto(s)
Anomalías Múltiples , Trastorno Autístico/genética , Cromosomas Humanos Par 16/ultraestructura , Cromosomas Humanos Par 7/ultraestructura , Translocación Genética , Quistes Aracnoideos , Trastorno Autístico/fisiopatología , Niño , Trastornos de la Conducta Infantil , Bandeo Cromosómico , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Trastornos de los Cromosomas/fisiopatología , Cromosomas Artificiales Bacterianos , Cisterna Magna/patología , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Trastornos PsicomotoresRESUMEN
Mental retardation occurs in 2-3% of the general population either in isolation or in combination with facial dysmorphism and/or malformations. Chromosomal abnormalities are a most common etiology. Karyotype displays chromosome aberrations in about 10% of patients but it has a limited resolution (5 Mb). Recently, the development of new molecular cytogenetic tools, especially array CGH, allowed to detect smaller abnormalities and increased the diagnosis capability of 15-20%. Among these newly detected rearrangements, some of them are recurrent and define new recognized syndromes. We will first briefly explain the non-allelic homologous recombination (NAHR) mechanism that underlines the origin of recurrent microdeletions and microduplications. Then we will describe eight new syndromes, four microdeletions (del 17q21.31, del 3q29, del 15q24, del 2q32.3q33) and four microduplications (dup 22q11.2, dup 7q11.23, dup 17p11.2, duplication of MECP2). A better knowledge of these new recurrent chromosomal syndromes will allow to improve care for patients, to develop targeted chromosomal diagnosis and to identify genes involved in neurocognitive functions.
Asunto(s)
Trastornos de los Cromosomas/clasificación , Anomalías Múltiples/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 15/ultraestructura , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 17/ultraestructura , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 2/ultraestructura , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 3/ultraestructura , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/ultraestructura , Duplicación de Gen , Humanos , Discapacidad Intelectual/genética , Cariotipificación , Proteína 2 de Unión a Metil-CpG/genética , Hibridación de Ácido Nucleico , Recombinación Genética , Eliminación de Secuencia , SíndromeRESUMEN
Aggressive natural killer cell leukemia (ANKL) is a very rare condition and when reported occurs almost exclusively in adults. We report a pediatric case of ANKL that presented with hemophagocytic syndrome, preceding the onset of leukemia by 12 weeks. Clinical and laboratory findings are discussed, along with morphology, immunophenotyping and cytogenetics, as well as the association with Epstein-Barr virus (EBV). This case is noteworthy for the expression of CD8 on the malignant cells, the cytogenetic findings that include abnormalities of chromosomes 6 and 7, as well as the age of the patient.