RESUMO
BACKGROUND: Non-epithelial gonadal tumours largely comprise sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Specific somatic mutations in DICER1, a microRNA maturation pathway gene, have been identified in these tumours. We conducted a study that aimed to confirm, refine and extend the previous observations. METHODS: We used Sanger sequencing to sequence the RNase IIIa and IIIb domains of DICER1 in 154 gonadal tumours from 135 females and 19 males, as well as 43 extra-gonadal GCTs from 26 females and 17 males. RESULTS: We identified heterozygous non-synonymous mutations in the RNase IIIb domain of DICER1 in 14/197 non-epithelial tumours (7.1%). Mutations were found in 9/28 SCSTs (32%), 5/118 gonadal GCTs (4.2%), 0/43 extra-gonadal GCTs and 0/8 miscellaneous tumours. The 14 mutations affected only five residues: E1705, D1709, E1788, D1810 and E1813. In all five patients where matched and constitutional DNA was available, the mutations were only somatic. There were no mutations found in the RNase IIIa domain. CONCLUSION: More than half (8/15) of Sertoli-Leydig cell tumours (SLCTs) harbour DICER1 mutations in the RNase IIIb domain, while mutations are rarely found in GCTs. Genetic alterations in SLCTs may aid in classification and provide new approaches to therapy.
Assuntos
RNA Helicases DEAD-box/genética , Mutação , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Neoplasias Testiculares/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/epidemiologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/epidemiologia , Neoplasias Testiculares/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes. METHODS: A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays. RESULTS: Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a 'methylator' phenotype, including silencing of genes associated with Caspase-8-dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype. CONCLUSION: Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8-dependent cell death might explain the relative resistance of YSTs to conventional therapy.
Assuntos
Caspase 8/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Inativação Gênica , Genes Supressores de Tumor , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/genética , Apoptose , Criança , Pré-Escolar , Análise por Conglomerados , Resistencia a Medicamentos Antineoplásicos , Tumor do Seio Endodérmico/tratamento farmacológico , Tumor do Seio Endodérmico/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Germinoma/tratamento farmacológico , Germinoma/genética , Humanos , Masculino , Análise em Microsséries , Neoplasias Embrionárias de Células Germinativas/patologia , Fenótipo , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , DNA Metiltransferase 3BRESUMO
α-Fetoprotein (AFP) measurements have clinical implications in fetal medicine and, in infants and older children, in detection, differential diagnosis and monitoring of malignant disease. Maternal serum AFP levels constitute part of a multiple-marker test used in early second-trimester screening to predict risk of fetal chromosomal abnormalities. Those individuals with increased risk are offered further definitive diagnostic investigation. Second-trimester screening is now increasingly being superseded by first-trimester screening with other serum markers and ultrasound. As AFP is only produced physiologically during fetal development, elevated serum levels after the first two post-natal years usually indicate the presence of a malignant disease process. Before this time, levels may be purely physiological and therefore serial values should be plotted on a logarithmic chart to ensure that they are falling appropriately, with a typical half-life of â¼5-6 days. If not, further investigation should be undertaken. Serum AFP is raised in a significant proportion of germ cell tumours (GCTs), hepatoblastoma and hepatocellular carcinoma (HCC). In suspected cases of GCT, serum human choriogonadotropin (HCG) estimation should also be performed. For possible intracranial GCTs, both serum and cerebrospinal fluid levels of AFP and HCG should be measured, ideally before neurosurgical biopsy. In malignant conditions, serum AFP may be used for diagnosis, treatment monitoring, surveillance for disease recurrence and prognostication. Immunohistochemistry for AFP using antibody staining is routinely used to assist pathological diagnosis on tissue sections where the differential includes GCT, hepatoblastoma and/or HCC. Elevations of serum AFP also occur in non-malignant conditions such as chronic liver disease.
Assuntos
Complicações Neoplásicas na Gravidez/diagnóstico , Diagnóstico Pré-Natal/métodos , alfa-Fetoproteínas/análise , Feminino , Humanos , Gravidez , Complicações Neoplásicas na Gravidez/sangueRESUMO
INTRODUCTION: Leukaemia and lymphoma may present with symptoms and signs mimicking common respiratory conditions of childhood such as asthma or croup. The UK National Institute for Clinical Excellence guidelines for referral for suspected cancer state that "the primary healthcare professional should be ready to review the initial diagnosis in patients in whom common symptoms do not resolve as expected" and "must be alert to the possibility of cancer when confronted by unusual symptom patterns" (National Institute for Health and Clinical Excellence, 2005). RESULTS AND DISCUSSION: A child with an undiagnosed mediastinal mass presenting with signs and symptoms suggestive of asthma or croup may be given oral systemic steroids. We report four such illustrative cases presenting to a single institution within the last 3 years. CONCLUSION: We highlight key points from the history and examination findings which should lead to review of the original diagnosis, the benefit of early chest X-ray in such cases and the dangers of steroid pretreatment.
Assuntos
Linfoma/diagnóstico por imagem , Adolescente , Asma/diagnóstico , Criança , Crupe/diagnóstico , Diagnóstico Diferencial , Diagnóstico Precoce , Feminino , Humanos , Linfoma/diagnóstico , Masculino , Neoplasias do Mediastino/diagnóstico por imagem , Guias de Prática Clínica como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Radiografia , Doenças Respiratórias/diagnóstico por imagemRESUMO
Proinflammatory cytokines interleukin (IL)-1alpha, IL-6, IL-8, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been detected in tumor specimens and primary cell cultures from patients with head and neck squamous cell carcinoma. IL-1alpha has been reported to play an important role in inducing the expression of cytokines IL-6, IL-8, and GM-CSF during inflammation. We examined whether these cytokines are expressed together in five primary and seven established UM-SCC cell lines, and we also examined the effects of IL-1alpha, IL-1 receptor antagonist or neutralizing antibody (Ab) upon expression of this repertoire of proinflammatory cytokines in established UM-SCC lines. Secretion of proinflammatory cytokines IL-1alpha, IL-6, IL-8, and GM-CSF was detected by ELISA in both the primary and established UM-SCC lines. Constitutive expression of specific mRNAs for these cytokines was confirmed in the UM-SCC lines by reverse transcriptase-PCR and Northern blot analysis. Addition of recombinant IL (rIL)-1alpha but not rIL-6 induced a dose-dependent increase in IL-8 and GM-CSF production. IL-1 receptor antagonist (IL-RA) or anti-IL-1 neutralizing Ab could completely inhibit the rIL-1alpha-inducible increase in IL-8 and GM-CSF expression, but the inhibitors had a negligible effect on the constitutive level of production of the cytokines. Transfer and expression of the IL-1alpha gene in a low-cytokine-producing cell line, UM-SCC-38, induced IL-8 and GM-CSF expression, but this expression was also not inhibited by IL-1RA or anti-IL-1 neutralizing Ab. We conclude that IL-1alpha can enhance the expression of cytokines IL-8 and GM-CSF in UM-SCC cell lines but that constitutive expression of these cytokines by UM-SCC is not inhibited by exogenous IL-1RA or neutralizing Ab.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Interleucinas/metabolismo , Proteínas de Neoplasias/metabolismo , Adulto , Idoso , Anticorpos/farmacologia , Northern Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-1/farmacologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Interleucinas/antagonistas & inibidores , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/farmacologia , Reação em Cadeia da Polimerase , Proteínas Recombinantes/farmacologia , Transfecção , Células Tumorais CultivadasRESUMO
Genomic and protein-coding transcriptomic data have suggested that germ cell tumours (GCTs) of childhood are biologically distinct from those of adulthood. Global messenger RNA profiles segregate malignant GCTs primarily by histology, but then also by age, with numerous transcripts showing age-related differential expression. Such differences are likely to account for the heterogeneous clinico-pathological behaviour of paediatric and adult malignant GCTs. In contrast, as global microRNA signatures of human tumours reflect their developmental lineage, we hypothesized that microRNA profiles would identify common biological abnormalities in all malignant GCTs owing to their presumed shared origin from primordial germ cells. MicroRNAs are short, non-protein-coding RNAs that regulate gene expression via translational repression and/or mRNA degradation. We showed that all malignant GCTs over-express the miR-371-373 and miR-302/367 clusters, regardless of patient age, histological subtype or anatomical tumour site. Furthermore, bioinformatic approaches and subsequent Gene Ontology analysis revealed that these two over-expressed microRNAs clusters co-ordinately down-regulated genes involved in biologically significant pathways in malignant GCTs. The translational potential of this finding has been demonstrated with the detection of elevated serum levels of miR-371-373 and miR-302/367 microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment. The tumour-suppressor let-7 microRNA family has also been shown to be universally down-regulated in malignant GCTs, because of abundant expression of the regulatory gene LIN28. Low let-7 levels resulted in up-regulation of oncogenes including MYCN, AURKB and LIN28 itself, the latter through a direct feedback mechanism. Targeting LIN28, or restoring let-7 levels, both led to effective inhibition of this pathway. In summary, paediatric malignant GCTs show biological differences from their adult counterparts at a genomic and protein-coding transcriptome level, whereas they both display very similar microRNA expression profiles. These similarities and differences may be exploited for diagnostic and/or therapeutic purposes.
Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/genética , Neoplasias Testiculares/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Fenótipo , Prognóstico , Fatores de Risco , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/patologia , Neoplasias Testiculares/terapiaRESUMO
Malignant germ cell tumours (MGCTs) of childhood are a rare group of neoplasms that comprise many histological subtypes and arise at numerous different sites. Genomic imbalances have been described in these tumours but, largely because of the paucity of cases reported in the literature, it is unclear how they relate to abnormalities in adult MGCTs and impact on potential systems for classifying GCTs. We have used metaphase-based comparative genomic hybridisation to analyse the largest series of paediatric MGCTs reported to date, representing 34 primary tumours (22 yolk sac tumours (YSTs), 11 germinomatous tumours and one metastatic embryonal carcinoma) occurring in children from birth to age 16, including 17 ovarian MGCTs. The large dataset enabled us to undertake statistical analysis, with the aim of identifying associations worthy of further investigation between patterns of genomic imbalance and clinicopathological parameters. The YSTs showed an increased frequency of 1p- (P=0.003), 3p+ (P=0.02), 4q- (P=0.07) and 6q- (P=0.004) compared to germinomatous tumours. Gain of 12p, which is invariably seen in adult MGCTs, was present in 53% of primary MGCTs of children aged 5-16 and was also observed in four of 14 YSTs affecting children less than 5. Two of these cases (14% of MGCTs in children less than 5) showed gain of the 12p11 locus considered to be particularly relevant in adult MGCTs. Gain of 12p showed a significant association with gain of 12q. Conversely, MGCTs without 12p gain displayed a significantly increased frequency of loss on 16p (P=0.04), suggesting that this imbalance may contribute to tumour development in such cases. This data provides new insight into the biology of this under-investigated tumour group and will direct future studies on the significance of specific genetic abnormalities.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 12/genética , Neoplasias Embrionárias de Células Germinativas/genética , Adolescente , Criança , Pré-Escolar , Seguimentos , Humanos , Lactente , Recém-Nascido , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/diagnósticoRESUMO
A girl with acute lymphoblastic leukemia in remission had two seizures during the maintenance phase of her treatment. Magnetic resonance imaging with angiography identified a superior sagittal sinus thrombosis as the likely explanation for her symptoms. Possible causes are considered, and previous reports of the neurotoxicity of agents used in the treatment of leukemia are reviewed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Embolia e Trombose Intracraniana/diagnóstico , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adulto , Ataxia , Neoplasias do Sistema Nervoso Central/prevenção & controle , Feminino , Humanos , Injeções Espinhais , Embolia e Trombose Intracraniana/induzido quimicamente , Angiografia por Ressonância Magnética , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prednisolona/administração & dosagem , Convulsões , Vincristina/administração & dosagemRESUMO
The objective of this study was to test the hypothesis that chromosomal imbalances in central nervous system primitive neuroectodermal tumours (PNETs) reflect site and histology. We used comparative genomic hybridization to study 37 cases of PNET, of which four were cerebral and 31 were medulloblastomas classified histologically as classic (n = 17) or nodular/desmoplastic (n = 14). Tumour immunophenotype was characterized with antibodies to neuroglial, mesenchymal and epithelial markers. Chromosomal imbalances were detected in 28 medulloblastomas (90%), and significant associations between tumour variants and genetic abnormalities were demonstrated. Aberrations suggesting isochromosome 17q were present in eight (26%) medulloblastomas, of which seven were classic variants. None of these cases, or a further six with gain of 17q, showed immunoreactivity for glial fibrillary acidic protein. Loss on 9q was found in six cases (19%), five of them nodular/desmoplastic. Loss of 22 occurred in four (13%), all classic medulloblastomas in young patients with a poor outcome and immunoreactivity for more than one epithelial or mesenchymal marker. Different patterns of imbalance were found in the cerebral PNETs. There were no abnormalities of chromosome 17, but all three cases with imbalance showed losses of 3p12.3-p14.
Assuntos
Neoplasias Encefálicas/genética , Aberrações Cromossômicas , Tumores Neuroectodérmicos Primitivos/genética , Adolescente , Adulto , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Proteína Glial Fibrilar Ácida/análise , Humanos , Imuno-Histoquímica , Lactente , Tumores Neuroectodérmicos Primitivos/mortalidade , Tumores Neuroectodérmicos Primitivos/patologia , Hibridização de Ácido NucleicoRESUMO
We report the use of vincristine to treat a large steroid resistant haemangioma of the lower face and neck. At the time of treatment the lesion had shown no signs of involution. The haemangioma was not life threatening but extension within the mouth was associated with bleeding and ulceration, which was impairing feeding and speech development. A significant improvement was seen with vincristine treatment.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Hemangioma/tratamento farmacológico , Vincristina/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Neoplasias de Cabeça e Pescoço/patologia , Hemangioma/patologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Prednisolona/uso terapêuticoRESUMO
Several disorders of hypomagnesaemia of hetary renal origin are now recognised. The cases of two sisters from a consanguineous marriage with the syndrome of renal magnesium wasting, hypercalciuria and nephrocalcinosis are presented. Pathological examination of the heterozygous parental kidneys revealed mild focal interstitial fibrosis. This condition is a previously unreported cause of end-stage renal failure in childhood, and this report suggests that transplantation from heterozygous parental donors can be successfully undertaken without recurrence of the syndrome.
Assuntos
Cálcio/urina , Falência Renal Crônica/etiologia , Magnésio/sangue , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/genética , Criança , Consanguinidade , Feminino , Humanos , Falência Renal Crônica/terapia , Transplante de Rim/fisiologia , Erros Inatos do Metabolismo dos Metais/metabolismo , Nefrocalcinose/etiologiaRESUMO
Cytogenetically visible interstitial duplications of proximal 15q, which lack the Prader-Willi Angelman critical region (PWACR) frequently segregate in families without phenotypic effect, but the nature of the extra euchromatin has remained unclear. We used comparative genome hybridisation to confirm that the extra material in a cytogenetic triplication originated from proximal 15q. A PAC clone containing sequences specific for the type-1 neurofibromatosis (NF-1) pseudogenes, which map to 15q11.2, hybridised along the length of the enlarged region between the PWACR and the centromere. Computerised measurement of the fluorescent signal from the enlarged and normal chromosomes gave an average ratio of 9.85:1, consistent with amplification. In a second family, an amplified P1-4 signal co-segregated with a cytogenetic duplication and the average ratio between amplified and normal signals in the proband was 8.22:1. Ratios in noncarrier family members and control individuals were close to unity in most cases, but significantly greater than one in at least one instance. Our results provide a novel explanation for cytogenetic variation in 15q11.2. They also suggest that NF-1 pseudogene copy number may be polymorphic in the normal population, and that high copy numbers can produce G bands which do not reflect those of the normal constitutional karyotype.
Assuntos
Cromatina/genética , Cromossomos Humanos Par 15/genética , Amplificação de Genes/genética , Genes da Neurofibromatose 1/genética , Pseudogenes/genética , Adolescente , Bandeamento Cromossômico , Eucromatina , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , LinhagemRESUMO
OBJECTIVE: African American children have earlier pubertal and skeletal maturation and a higher body mass index (BMI) than Caucasian children. We tested the hypothesis that advanced bone age in African American children is accounted for by their greater adiposity. STUDY DESIGN: We studied 252 African American (n = 97) and Caucasian (n = 155) children aged 5 to 12 years. Skeletal age was determined by a radiologist blinded to clinical details. The difference between bone age (BA) and chronological age (CA) (noted as BA - CA) and the ratio of bone age to chronological age (BA/CA) were determined. Analysis of covariance was used to adjust skeletal maturation for the effects of adiposity, as measured by BMI, BMI standard deviation score (BMI SDS), and fat mass by dual energy x-ray absorptiometry (DXA). RESULTS: African American children were significantly heavier than Caucasians (BMI SDS 2.7 +/- 3.4 vs 1.7 +/- 2.4, P <.05). Both BA - CA (0.75 +/- 1.46 vs 0.28 +/- 1.38, P <.05) and BA/CA (1.09 +/- 0.17 vs 1.03 +/- 0.16, P <.05) were significantly greater in African Americans than Caucasians. BA - CA and BA/CA were significantly correlated with lean body mass, BMI, BMI SDS, and DXA fat mass (all r > 0.46, P <.001). Neither BA - CA nor BA/CA of African Americans and Caucasians were significantly different after correction for lean body mass and measures of adiposity, including BMI, BMI SDS, or DXA fat mass. CONCLUSION: Skeletal age is more advanced in African American than Caucasian children and is significantly related to body mass. In large measure, the advancement in skeletal maturation of prepubertal and early pubertal African American children can be accounted for by their greater adiposity.
Assuntos
Tecido Adiposo/crescimento & desenvolvimento , População Negra/genética , Desenvolvimento Ósseo/genética , População Branca/genética , Absorciometria de Fóton , Tecido Adiposo/diagnóstico por imagem , Determinação da Idade pelo Esqueleto , Análise de Variância , Estatura/genética , Índice de Massa Corporal , Peso Corporal/genética , Criança , Desenvolvimento Infantil , Pré-Escolar , Feminino , Humanos , Masculino , Obesidade/diagnóstico por imagem , Obesidade/genética , Puberdade/genéticaRESUMO
We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.
Assuntos
Cromossomos Humanos Par 15/genética , Família Multigênica , Adulto , Síndrome de Angelman/genética , Pré-Escolar , Cromossomos Humanos Par 15/ultraestrutura , Cosmídeos , Doenças em Gêmeos , Feminino , Doenças Fetais/genética , Impressão Genômica , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Masculino , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Síndrome de Prader-Willi/genéticaRESUMO
PROCEDURE: Analysis of comparative genomic hybridization (CGH) data of 120 tumors from four different studies, and data of 84 previously unpublishied tumors, allowed delineation of at least six different genetic subsets of neuroblastomas. RESULTS AND CONCLUSIONS: A small number of tumors show no detectable imballances. A second group of tumors presents with gains and losses of whole chromosomes and is found predominantly in prognostically favorable stage 1 and 2 tumors. The remaining groups are characterized by the presence of partial chromosome imbalances, and are found mostly in stage 3, 4, and 4S tumors. The third group shows 17q gain without 11q loss, 1p loss, or MYCN amplification (MNA). The fourth group has 1p deletion or MNA, and finally, a fifth group shows 11q loss without 1p deletion or MNA, and is found mainly in stage 4 tumors. The latter group is significantly associated with losses of 3p, 4p, and 14q.
Assuntos
Aberrações Cromossômicas , DNA de Neoplasias/análise , Neuroblastoma/genética , Deleção Cromossômica , Cromossomos Humanos/genética , Cromossomos Humanos/ultraestrutura , Humanos , Perda de Heterozigosidade , Estadiamento de Neoplasias , Neuroblastoma/classificação , Neuroblastoma/mortalidade , Hibridização de Ácido Nucleico , Prognóstico , TrissomiaRESUMO
The purpose of this study was to determine the ability of air displacement plethysmography (ADP) to estimate body fatness in prepubertal and early pubertal African American and white children. One hundred nineteen nonoverweight and overweight boys (N = 56) and girls (N = 63), age (mean +/- SD) 9.8 +/- 1.7 y, body mass index 25.9 +/- 7.6 kg/m2 (range, 14.2-47.0 kg/m2), and mean percent body fat (%BF) by dual-energy x-ray absorptiometry (DXA) 39.2 +/- 11.7% (range, 12.2-57.5%), were studied. %BF by ADP was compared with DXA %BF estimates and with body fat by several field methods: skinfold thicknesses using the Slaughter et al. equations (Hum Biol 60: 709-723, 1988), bioelectrical impedance analysis (BIA) using the Houtkooper et al. equation (J Appl Physiol 72: 366-373, 1992), and a predictive equation using skinfold thicknesses, BIA, and weight (Goran et al.: Am J Clin Nutr 63: 299-305, 1996). All methods used to estimate %BF were significantly correlated with DXA (all p < 0.0001), with r2 ranging from 0.85 (skinfold measurements) to 0.95 (ADP). ADP using the Siri equation underestimated %BF by -1.9% (p < 0.001); the Bland-Altman limits of agreement (defined as +/-2 SD) were +/-7.4%. %BF by ADP-Siri underestimated %BF by DXA by 3.0% for girls (p < 0.001) and by 0.6% for boys (NS). Agreement between body fat estimation by ADP and DXA did not vary with age, race, or pubertal stage. Application of the age-adjusted Lohman model to ADP significantly increased the magnitude of the underestimation to -6.9% (p < 0.0001). Prediction of %BF by the Slaughter skinfold thickness equation showed no significant mean bias for the overall data, but significantly underestimated %BF in girls (-3.7%) while overestimating %BF in boys (+2.4%) with wide limits of agreement (+/-17.7%, p < 0.01 versus ADP). %BF by the Houtkooper BIA equation or Goran model underestimated %BF to a significantly greater degree than ADP (Houtkooper, -8.1%; Goran, -10.1%; both p < 0.0001 versus DXA or ADP). Determination of %BF from ADP using the Siri model slightly underestimates %BF as determined by DXA in girls, but appears to be superior to existing field methods both in accuracy and limits of agreement. Because of the ease with which it can be performed, ADP may prove useful for investigations of adiposity in children.
Assuntos
Tecido Adiposo , População Negra , Composição Corporal , Pletismografia/métodos , População Branca , Antropometria , Criança , Feminino , Humanos , MasculinoRESUMO
We present seven families with a cytogenetic duplication of the short arm of chromosome 8 at band 8p23.1. The duplication has been transmitted from parents to offspring in four of the seven families. In three families, the source of the extra material and its euchromatic origin were established using FISH with a YAC which was mapped to 8p23.1 and a whole chromosome paint for chromosome 8. FISH signals from this YAC were significantly larger on the duplicated chromosome compared with the normal chromosome in all six family members tested. Comparative genomic hybridisation (CGH) on a representative subject was consistent with these results. The families were ascertained for a variety of mostly incidental reasons including prenatal diagnosis for advanced maternal age. The transmission of this duplication by multiple phenotypically normal family members with no history of reproductive loss suggests the existence of a novel class of 8p23.1 duplications, which can be regarded as euchromatic variants or duplications with no phenotypic effect.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 8 , Rearranjo Gênico , Família Multigênica , Adulto , Amniocentese , Criança , Bandeamento Cromossômico , Mapeamento Cromossômico , Cromossomos Artificiais de Levedura , Síndrome de Down/genética , Feminino , Triagem de Portadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Linhagem , GravidezRESUMO
We have studied the occurrence and association of 11q deletions with other chromosomal imbalances in Stage 4 neuroblastomas. To this purpose we have performed comparative genomic hybridization (CGH) analysis on 50 Stage 4 neuroblastomas and these data were analyzed together with those from 33 previously published cases. We observed a high incidence of 11q deletion in Stage 4 neuroblastoma without MYCN amplification (59%) whereas 11q loss was only observed in 15% of neuroblastomas with MYCN-amplification (p = 0.0002) or 11% of cases with 1p deletion detected by CGH (p = 0.0001). In addition, 11q loss showed significant positive correlation with 3p loss (p = 0.0002). Event-free survival was poor and not significantly different for patients with or without 11q deletion. Our study provides further evidence that Stage 4 neuroblastomas with 11q deletions represent a distinct genetic subgroup that typically shows no MYCN-amplification nor 1p deletion. Moreover, it shows that neuroblastomas with 11q deletion also often present 3p deletion. This genetic subgroup shows a similar poor prognosis as MYCN amplified 4 neuroblastomas.