Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 1/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Pneumonia em Organização Criptogênica/etiologia , Síndromes Mielodisplásicas/complicações , Idoso , Pneumonia em Organização Criptogênica/diagnóstico por imagem , Pneumonia em Organização Criptogênica/tratamento farmacológico , Pneumonia em Organização Criptogênica/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prednisolona/uso terapêutico , Estudos RetrospectivosRESUMO
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.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 7/genética , Coloboma/genética , Anormalidades Congênitas/genética , Dupla Via de Saída do Ventrículo Direito/genética , Duplicação Gênica , Disostose Mandibulofacial/genética , Microftalmia/genética , Disco Óptico/anormalidades , Adulto , Cromossomos Humanos Par 7/ultraestrutura , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Masculino , Proteínas de Membrana/genética , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome , Artérias Umbilicais/anormalidadesRESUMO
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.
Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos X/genética , Epilepsias Mioclônicas/genética , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Adulto , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Cromossomos Humanos X/ultraestrutura , Consanguinidade , Variações do Número de Cópias de DNA , Feminino , Duplicação Gênica , Estudos de Associação Genética , Humanos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Linhagem , Receptores de Citocinas/genética , Deleção de Sequência , Análise Serial de Tecidos , Receptor Nicotínico de Acetilcolina alfa7/genéticaRESUMO
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.
Assuntos
Anormalidades Múltiplas/genética , Acrocefalossindactilia/genética , Cromossomos Humanos Par 2/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Proteínas do Tecido Nervoso/deficiência , Proteínas Nucleares/deficiência , Proteína Gli2 com Dedos de Zinco/deficiência , Proteína Gli3 com Dedos de Zinco/deficiência , Adolescente , Pré-Escolar , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 7/genética , Fissura Palatina/genética , Nanismo/genética , Feminino , Intolerância à Glucose/genética , Proteínas Hedgehog/fisiologia , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Deficiência Intelectual/genética , Cariotipagem , Modelos Biológicos , Morfogênese/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Deleção de Sequência , Transdução de Sinais/genética , Síndrome , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/fisiologia , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/fisiologiaAssuntos
Transformação Celular Neoplásica/genética , Deleção Cromossômica , Cromossomos Humanos Par 7/ultraestrutura , Deleção de Genes , Leucemia Mieloide Aguda/etiologia , Linfoma Folicular/terapia , Linfoma de Célula do Manto/terapia , Síndromes Mielodisplásicas/etiologia , Segunda Neoplasia Primária/etiologia , Transplante de Células-Tronco de Sangue Periférico , Cromossomos em Anel , Aloenxertos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Biomarcadores Tumorais , Medula Óssea/patologia , Cromossomos Humanos Par 7/genética , Ciclofosfamida/administração & dosagem , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Doadores Vivos , Linfoma Folicular/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Segunda Neoplasia Primária/patologia , Proteínas Proto-Oncogênicas c-ets/deficiência , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Rituximab , Quimeras de Transplante/genética , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Variante 6 da Proteína do Fator de Translocação ETSAssuntos
Deleção Cromossômica , Cromossomos Humanos Par 11/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Leucemia Mieloide Aguda/genética , Translocação Genética , Trissomia , Idoso , Bandeamento Cromossômico , Coloração Cromossômica , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 7/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Dosagem de Genes , Histona-Lisina N-Metiltransferase , Humanos , Masculino , Proteína de Leucina Linfoide-Mieloide/genéticaRESUMO
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.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 7/genética , Glioblastoma/genética , Glioblastoma/patologia , Oligodendroglioma/genética , Oligodendroglioma/patologia , Adulto , Neoplasias Encefálicas/cirurgia , Cromossomos Humanos Par 1/ultraestrutura , Cromossomos Humanos Par 10/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Citogenética , Feminino , Glioblastoma/cirurgia , Humanos , Imuno-Histoquímica , Oligodendroglioma/cirurgia , Telômero/genética , Telômero/ultraestruturaAssuntos
Crise Blástica/genética , Cromossomos Humanos Par 12/ultraestrutura , Cromossomos Humanos Par 14/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Cromossomos Humanos Par 9/ultraestrutura , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Translocação Genética , Adulto , Medula Óssea/patologia , Bandeamento Cromossômico , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 9/genética , Erros de Diagnóstico , Humanos , Hibridização in Situ Fluorescente , Linfonodos/patologia , Masculino , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMO
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.
Assuntos
Carcinoma de Células de Transição/genética , Aberrações Cromossômicas , Hibridização in Situ Fluorescente , Recidiva Local de Neoplasia/genética , Neoplasias da Bexiga Urinária/genética , Algoritmos , Aneuploidia , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/epidemiologia , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/terapia , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 3/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Cromossomos Humanos Par 9/genética , Cromossomos Humanos Par 9/ultraestrutura , Cistoscopia , Feminino , Seguimentos , Humanos , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Teste de Papanicolaou , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Urina/citologiaAssuntos
Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Mapeamento Cromossômico , Cromossomos Humanos Par 2/ultraestrutura , Cromossomos Humanos Par 3/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Feminino , Genes myc , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Alemanha/epidemiologia , Humanos , Masculino , Mieloma Múltiplo/epidemiologia , Risco , Reino Unido/epidemiologiaRESUMO
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.
Assuntos
Cromossomos Humanos Par 7/genética , Genes Supressores de Tumor , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Fatores Reguladores de Interferon/genética , Linfoma de Zona Marginal Tipo Células B/genética , Proteínas de Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Deleção de Sequência , Neoplasias Esplênicas/genética , Animais , Apoptose/genética , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/transplante , Cromossomos Humanos Par 7/ultraestrutura , Hibridização Genômica Comparativa , Regulação Neoplásica da Expressão Gênica , Genes de Imunoglobulinas , Humanos , Fatores Reguladores de Interferon/biossíntese , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/fisiologia , Estimativa de Kaplan-Meier , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia , Mutação Puntual , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Esplênicas/mortalidade , Neoplasias Esplênicas/patologia , Translocação GenéticaRESUMO
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.
Assuntos
Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 7/genética , DNA/análise , Endopeptidases/genética , Tiques/genética , Síndrome de Tourette , Apraxias/genética , Apraxias/fisiopatologia , Cromossomos Humanos Par 7/ultraestrutura , Hibridização Genômica Comparativa , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Endopeptidases/metabolismo , Éxons , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Deleção de Sequência , Tiques/fisiopatologia , Síndrome de Tourette/genética , Síndrome de Tourette/fisiopatologia , Translocação GenéticaRESUMO
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.
Assuntos
Deleção Cromossômica , Mapeamento Cromossômico , Anemia de Fanconi/complicações , Anemia de Fanconi/genética , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos/ultraestrutura , Cromossomos Humanos Par 3/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , RiscoRESUMO
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.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 7/ultraestrutura , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mutação , Polirribossomos/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)RESUMO
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.
Assuntos
Técnicas de Cultura de Células/métodos , Cromossomos Humanos Par 19/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Neurônios/citologia , Células-Tronco/citologia , Trissomia , Encéfalo/embriologia , Aberrações Cromossômicas , Citogenética , Células-Tronco Embrionárias/citologia , Receptores ErbB/metabolismo , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Análise de Sequência com Séries de OligonucleotídeosAssuntos
Azatioprina/efeitos adversos , Cromossomos Humanos Par 1/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Síndrome Hipereosinofílica/tratamento farmacológico , Imunossupressores/efeitos adversos , Leucemia Eritroblástica Aguda/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azatioprina/administração & dosagem , Azatioprina/uso terapêutico , Medula Óssea/patologia , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 7/genética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Evolução Fatal , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Eritroblástica Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Neutropenia/etiologia , Choque Séptico/etiologiaRESUMO
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.
Assuntos
Anormalidades Múltiplas , Transtorno Autístico/genética , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 7/ultraestrutura , Translocação Genética , Cistos Aracnóideos , Transtorno Autístico/fisiopatologia , Criança , Transtornos do Comportamento Infantil , Bandeamento Cromossômico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Transtornos Cromossômicos/fisiopatologia , Cromossomos Artificiais Bacterianos , Cisterna Magna/patologia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Transtornos PsicomotoresRESUMO
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.
Assuntos
Transtornos Cromossômicos/classificação , Anormalidades Múltiplas/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 11/ultraestrutura , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 2/ultraestrutura , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 3/ultraestrutura , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 7/ultraestrutura , Duplicação Gênica , Humanos , Deficiência Intelectual/genética , Cariotipagem , Proteína 2 de Ligação a Metil-CpG/genética , Hibridização de Ácido Nucleico , Recombinação Genética , Deleção de Sequência , SíndromeRESUMO
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.