RESUMO
PURPOSE: The benefit of whole brain radiotherapy (WBRT) for late stage breast cancer patients with brain metastases has been questioned. In this study we evaluated survival and level of care (hospital or home) following WBRT in a population-based cohort by personal and tumor characteristics. METHODS: We identified 241 consecutive patients with breast cancer and brain metastases receiving WBRT in Stockholm, Sweden, 1999-2012. Through review of medical records, we collected data on prognostic determinants including level of care before and after WBRT. Survival was estimated using Cox regression, and odds ratios (OR) of not coming home using logistic regression. RESULTS: Median age at WBRT was 58 years (range 30---88 years). Most patients (n = 212, 88%) were treated with 4 Gray × 5. Median survival following WBRT was 2.9 months (interquartile range 1.1-6.6 months), and 57 patients (24%) were never discharged from hospital. Poor performance status and triple-negative tumors were associated with short survival (WHO 3-4 median survival 0.9 months, HR = 5.96 (3.88-9.17) versus WHO 0-1; triple-negative tumors median survival 2.0 months, HR = 1.87 (1.23-2.84) versus Luminal A). Poor performance status and being hospitalized before WBRT were associated with increased ORs of not coming home whereas cohabitation with children at home was protective. CONCLUSION: Survival was short following WBRT, and one in four breast cancer patients with brain metastases could never be discharged from hospital. When deciding about WBRT, WHO score, level of care before WBRT, and the patient's choice of level of care in the end-of-life period should be considered.
Assuntos
Neoplasias Encefálicas/radioterapia , Encéfalo/patologia , Neoplasias da Mama/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/efeitos da radiação , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Seleção de Pacientes , Suécia/epidemiologia , Assistência TerminalRESUMO
We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.
Assuntos
Transtorno Bipolar/genética , Transtornos Psicóticos/genética , Aminopeptidases/genética , Anquirinas/genética , Transtorno Bipolar/classificação , Transtorno Bipolar/psicologia , Canais de Cálcio Tipo L/genética , Proteínas de Ligação a Calmodulina/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 10/genética , Proteínas do Citoesqueleto , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/psicologiaRESUMO
Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1ß and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
Assuntos
Transtorno Bipolar/genética , Ácido Cinurênico/metabolismo , Transtornos Psicóticos/genética , Adulto , Idoso , Transtorno Bipolar/líquido cefalorraquidiano , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Cromossomos Humanos Par 1/genética , Transtornos Cognitivos/complicações , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Ácido Cinurênico/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/complicações , Transtornos Psicóticos/metabolismo , Nexinas de Classificação/genéticaRESUMO
Glioblastoma (GBM) is a devastating tumor and few patients survive beyond 3 years. Defining the molecular determinants underlying long-term survival is essential for insights into tumor biology and biomarker identification. We therefore investigated homogeneously treated, IDH (wt) long-term (LTS, n = 10) and short-term survivors (STS, n = 6) by microarray transcription profiling. While there was no association of clinical parameters and molecular subtypes with long-term survival, STS tumors were characterized by differential polarization of infiltrating microglia with predominance of the M2 phenotype detectable both on the mRNA and protein level. Furthermore, transcriptional signatures of LTS and STS predicted patient outcome in a large, IDH (wt) cohort (n = 468). Interrogation of overlapping genomic alterations identified concurrent gain of chromosomes 19 and 20 as a favorable prognostic marker. The strong association of this co-gain with survival was validated by aCGH in a second, independent cohort (n = 124). Finally, FISH and gene expression data revealed gains to constitute low-amplitude, clonal events with a strong impact on transcription. In conclusion, these findings provide important insights into the manipulation of the innate immune system by particularly aggressive GBM tumors. Furthermore, we genomically characterize a previously unknown, clinically relevant subgroup of glioblastoma, which can easily be identified through modern neuropathological workup.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 20 , Glioblastoma/genética , Glioblastoma/metabolismo , Adulto , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Estudos de Coortes , Feminino , Glioblastoma/diagnóstico , Glioblastoma/patologia , Humanos , Isocitrato Desidrogenase/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Microglia/metabolismo , Microglia/patologia , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/metabolismo , Análise de Sobrevida , Sobreviventes , Fatores de Tempo , Transcrição GênicaRESUMO
The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P=0.005, n=19) or schizophrenia (P=0.02, n=36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P=0.03) and reduced lymphoblastoid and hippocampal KMO expression (P≤0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.
Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Ácido Cinurênico/líquido cefalorraquidiano , Quinurenina 3-Mono-Oxigenase/biossíntese , Quinurenina 3-Mono-Oxigenase/genética , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Adulto , Idoso , Alelos , Transtorno Bipolar/complicações , Transtorno Bipolar/diagnóstico , Estudos de Casos e Controles , Linhagem Celular , Feminino , Expressão Gênica , Predisposição Genética para Doença/genética , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Transtornos Psicóticos/complicações , Esquizofrenia/líquido cefalorraquidiano , Esquizofrenia/metabolismo , Adulto JovemRESUMO
Telomere shortening is a hallmark of aging and has been associated with oxidative stress, inflammation and chronic somatic, as well as psychiatric disorders, including schizophrenia and depression. Additionally, antidepressants have been found to protect against telomere shortening. However, pharmacological telomere studies are lacking in bipolar disorder (BD). Therefore, the objective of this study was to explore telomere length (TL) in patients with BD in the context of lithium treatment. We determined TL by quantitative real-time PCR using peripheral blood leukocytes. Participants were outpatients diagnosed with BD type 1 or 2 (n=256) and healthy controls (n=139). Retrospective case-control and case-case study designs were applied. Lithium response (LiR) was scored using the Alda-Scale. Lithium-treated BD patients overall, as well as those on lithium monotherapy, had 35% longer telomeres compared with controls (P<0.0005, partial η(2)=0.13). TL correlated positively with lithium treatment duration of >30 months (P=0.031, R(2)=0.13) and was negatively associated with increasing number of depressive episodes (P<0.007). BD patients responding well to lithium treatment had longer telomeres than those not responding well. This is the first study to report a positive effect of long-term lithium treatment on TL. Importantly, longer TL was also associated with a better LiR in BD patients. These data suggest that lithium exerts a protective effect against telomere shortening especially when therapeutically efficacious. We hypothesize that induction of telomerase activity may be involved in LiR in BD.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Compostos de Lítio/uso terapêutico , Homeostase do Telômero/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Telômero/efeitos dos fármacos , Adulto JovemRESUMO
Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.
Assuntos
Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Complexo Principal de Histocompatibilidade/genética , Esquizofrenia/genética , População Branca/genética , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único , SuéciaRESUMO
BACKGROUND: While treatment for breast cancer has been refined and overall survival has improved, there is concern that the incidence of brain metastases has increased. METHODS: We identified patients in Sweden with incident breast cancer 1998-2006 in the National Cancer Register, and matched these to the National Patient Register to obtain information on hospital admissions for distant metastases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed with Cox regression as estimates of relative risk. RESULTS: Among 50 528 breast cancer patients, 696 (1.4%) were admitted with brain metastases during median 3.5 years of follow-up. Admissions for other metastases were found in 3470 (6.9%) patients. Compared with the period 1998-2000, patients diagnosed with breast cancer 2004-2006 were at a 44% increased risk of being admitted with brain metastases (HR 1.44, 95% CI 1.13-1.85). CONCLUSION: The incidence of admissions with brain metastases in breast cancer patients was increasing in the mid-2000s in Sweden. These findings support a true increase in incidence of brain metastases among breast cancer patients.
Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Suécia/epidemiologia , TempoRESUMO
We have previously identified a region containing 16 CpGs within the MGMT CpG islands which is critical for the transcriptional control of MGMT (Malley, Acta Neuropathol 2011). To investigate the patterns and incidence of MGMT methylation in astrocytic and oligodendroglial tumors, we quantitatively assessed methylation at these 16 CpGs using bisulfite modification followed by pyrosequencing of 362 gliomas not treated with temozolomide, and correlated the findings with previously identified patterns of genetic abnormalities, patients' age and survival. The MGMT gene was considered to be methylated when the mean methylation of the 16 CpGs was 10% or higher. This cut-off value distinguished diffuse astrocytomas with high and low MGMT expression. Within each tumor type, the patterns of methylation were highly variable and also highly heterogeneous across the 16 CpGs. A high incidence of MGMT methylation was observed in all subtypes of gliomas included in this study. Among a subset of 97 tumors where conventional methylation-specific PCR (MSP) was also applied, methylation was detected by both methods in 54 tumors, while the pyrosequencing results identified a further 17 tumors. No additional cases were found using MSP alone, indicating that pyrosequencing is a robust method for methylation analysis. All tumors with IDH1/IDH2 mutations except two had MGMT methylation, while there were many tumors with MGMT methylation, particularly primary glioblastomas, which had no mutations of IDH1/2. We suggest that MGMT methylation may be one of the earliest events in the development of astrocytic and oligodendroglial tumors.
Assuntos
Astrocitoma/genética , Ilhas de CpG/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Oligodendroglioma/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Astrocitoma/mortalidade , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/mortalidade , Prognóstico , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase em Tempo Real , Taxa de Sobrevida , Adulto JovemRESUMO
We investigated the efficacy and safety of single-agent pegylated liposomal doxorubicin (PLD) as first-line treatment for elderly women with advanced breast cancer and evaluated predictive markers for response and toxicity. Twenty-five women ≥ 65 years received 40 mg/m(2) PLD every 28 days. Time to treatment failure (TTF), response rate, time to progression (TTP) and overall survival (OS) was calculated. The ABCB1 single nucleotide polymorphisms (SNP), tumor MRN complex, and TOPOIIα were analyzed. A mean of 7.4 cycles PLD were administered and TTF was 5.5 months and OS 20.6 months. ABCB1 SNPs were found to correlate to both efficacy and toxicity, while tumor expression of the MRN complex and TOPOIIα correlated to TTP. PLD is a safe and effective treatment for elderly breast cancer patients. Also potential predictive markers were identified.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Doxorrubicina/análogos & derivados , Polietilenoglicóis/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Hidrolases Anidrido Ácido , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Enzimas Reparadoras do DNA/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Proteínas HMGN/metabolismo , Humanos , Proteína Homóloga a MRE11 , Polietilenoglicóis/efeitos adversos , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Fatores de Tempo , Transativadores/metabolismo , Falha de TratamentoRESUMO
Diffuse astrocytomas (WHO grade II) typically present as slow-growing tumours showing significant cellular differentiation, but possessing a tendency towards malignant progression. They account for ~10% of all astrocytic tumours, with a peak incidence between 30 and 40 years of age. Median survival is reported as around 6-8 years. Mutations of TP53 and IDH1 have been described as genetic hallmarks, while copy number alterations are also relatively common. However, there is some evidence to suggest that these characteristics may vary with age. Here, we present an integrated clinicopathologic, genomic and transcriptomic analysis suggesting that paediatric and adult tumours are associated with distinct genetic signatures. For example, no childhood tumour showed mutation of IDH1/2 or TP53, virtually no copy number changes were seen, and MGMT methylation was absent. In contrast, adult tumours showed IDH1/2 mutation in 94% and TP53 mutation in 69% of cases, with multiple copy number alterations per case and hypermethylation of MGMT in the majority of tumours. These differences were associated with a worse prognosis in the adult patients. The expression array data also revealed a significant difference in the expression of a number of genes putatively involved in neural stem cell maintenance and CNS development, including DLL3, HES5, BMP2, TIMP1 and BAMBI. Genes involved in DNA replication and the cell cycle were also enriched in the adult tumours, suggesting that their more aggressive behaviour may be due to derivation from a more rapidly dividing, less differentiated cell type.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Isocitrato Desidrogenase/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Fatores Etários , Astrocitoma/patologia , Astrocitoma/fisiopatologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Criança , Variações do Número de Cópias de DNA , Metilação de DNA , Análise Mutacional de DNA/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Componente Principal , Análise de Sobrevida , Adulto JovemRESUMO
Current risk stratification schemas for medulloblastoma, based on combinations of clinical variables and histotype, fail to accurately identify particularly good- and poor-risk tumors. Attempts have been made to improve discriminatory power by combining clinical variables with cytogenetic data. We report here a pooled analysis of all previous reports of chromosomal copy number related to survival data in medulloblastoma. We collated data from previous reports that explicitly quoted survival data and chromosomal copy number in medulloblastoma. We analyzed the relative prognostic significance of currently used clinical risk stratifiers and the chromosomal aberrations previously reported to correlate with survival. In the pooled dataset metastatic disease, incomplete tumor resection and severe anaplasia were associated with poor outcome, while young age at presentation was not prognostically significant. Of the chromosomal variables studied, isolated 17p loss and gain of 1q correlated with poor survival. Gain of 17q without associated loss of 17p showed a trend to improved outcome. The most commonly reported alteration, isodicentric chromosome 17, was not prognostically significant. Sequential multivariate models identified isolated 17p loss, isolated 17q gain, and 1q gain as independent prognostic factors. In a historical dataset, we have identified isolated 17p loss as a marker of poor outcome and 17q gain as a novel putative marker of good prognosis. Biological markers of poor-risk and good-risk tumors will be critical in stratifying treatment in future trials. Our findings should be prospectively validated independently in future clinical studies.
Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/mortalidade , Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Meduloblastoma/genética , Meduloblastoma/mortalidade , Adolescente , Adulto , Neoplasias Cerebelares/terapia , Criança , Pré-Escolar , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Meduloblastoma/terapia , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
A major focus of brain cancer research today is to translate understanding of glioma biology into advances in treatment, by exploring the potential of target therapy. Here we investigated the ability of three compounds belonging to the chemical class of azo dyes (methyl red, methyl yellow, and helianthin) to inhibit glioblastoma (GB) cell growth in vitro. Our results showed that helianthin induced cytotoxicity in two GB cell cultures, cell lines 18 and 38, whereas methyl red and methyl yellow were not cytotoxic. The effect of helianthin on EGFR, IGF-1R, and their common intracellular signaling via PI3-K and ERK1/2 was also analyzed. Treatment with helianthin down-regulated EGFR and IGF-1R activity in both cell lines. Helianthin treatment blocked ERK1/2 phosphorylation without affecting PI3K activity in cell line 18 and reduced both PI3K and ERK1/2 in GB 38 cell line. The cell death was accompanied by degradation of PARP without affecting BCL2 expression in both GB cell cultures. Because of the genetic heterogeneity of malignant gliomas, we tested the effect of helianthin on other two primary GB lines (11 and 15) and two early-passage GB cultures (BT1GB and BT2GB), to assess the general nature of the anti-tumor effect of the drug in GB cells. We found that helianthin treatment induced cell death in all the GB cell cultures analyzed. To our knowledge, this is the first report indicating that helianthin can reduce GB cell growth.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Venenos de Cnidários/farmacologia , Citotoxinas/farmacologia , Glioblastoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Compostos Azo/farmacologia , Western Blotting , Neoplasias Encefálicas/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Humanos , Imunoprecipitação , Técnicas In Vitro , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , p-Dimetilaminoazobenzeno/farmacologiaRESUMO
We studied the status of chromosomes 1 and 19 in 363 astrocytic and oligodendroglial tumors. Whereas the predominant pattern of copy number abnormality was a concurrent loss of the entire 1p and 19q regions (total 1p/19q loss) among oligodendroglial tumors and partial deletions of 1p and/or 19q in astrocytic tumors, a subset of apparently astrocytic tumors also had total 1p/19q loss. The presence of total 1p/19q loss was associated with longer survival of patients with all types of adult gliomas independent of age and diagnosis (P = .041). The most commonly deleted region on 19q in astrocytic tumors spans 885 kb in 19q13.33-q13.41, which is telomeric to the previously proposed region. Novel regions of homozygous deletion, including a part of DPYD (1p21.3) or the KLK cluster (19q13.33), were observed in anaplastic oligodendrogliomas. Amplifications encompassing AKT2 (19q13.2) or CCNE1 (19q12) were identified in some glioblastomas. Deletion mapping of the centromeric regions of 1p and 19q in the tumors that had total 1p/19q loss, indicating that the breakpoints lie centromeric to NOTCH2 within the pericentromeric regions of 1p and 19q. Thus, we show that the copy number abnormalities of 1p and 19q in human gliomas are complex and have distinct patterns that are prognostically predictive independent of age and pathological diagnosis. An accurate identification of total 1p/19q loss and discriminating this from other 1p/19q changes is, however, critical when the 1p/19q copy number status is used to stratify patients in clinical trials.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Glioma/diagnóstico , Glioma/genética , Neoplasias Encefálicas/classificação , Aberrações Cromossômicas , Glioma/classificação , Humanos , PrognósticoRESUMO
We screened exon 4 of the gene isocitrate dehydrogenase 1 (NADP+), soluble (IDH1) for mutations in 596 primary intracranial tumors of all major types. Codon 132 mutation was seen in 54% of astrocytomas and 65% of oligodendroglial tumors but in only 6% of glioblastomas (3% of primary and 50% of secondary glioblastomas). There were no mutations in any other type of tumor studied. While mutations in the tumor protein p53 gene (TP53) and total 1p/19q deletions were mutually exclusive, IDH1 mutations were strongly correlated with these genetic abnormalities. All four types of mutant IDH1 proteins showed decreased enzymatic activity. The data indicate that IDH1 mutation combined with either TP53 mutation or total 1p/19q loss is a frequent and early change in the majority of oligodendroglial tumors, diffuse astrocytomas, anaplastic astrocytomas, and secondary glioblastomas but not in primary glioblastomas.
Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Oligodendroglioma/genética , Adulto , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Hibridização Genômica Comparativa , Éxons/genética , Genótipo , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Perda de Heterozigosidade , Oligodendroglioma/enzimologia , Oligodendroglioma/patologia , Prognóstico , Proteína Supressora de Tumor p53/genéticaAssuntos
Transtorno Bipolar/economia , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Feminino , Hospitais Psiquiátricos/estatística & dados numéricos , Humanos , Pacientes Internados , Tempo de Internação/economia , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/economia , Admissão do Paciente/estatística & dados numéricos , Unidade Hospitalar de Psiquiatria/estatística & dados numéricos , SuéciaRESUMO
Brain tumors are the most common solid tumors of childhood, and pilocytic astrocytomas (PA) are the most common central nervous system tumor in 5 to 19 year olds. Little is known about the genetic alterations underlying their development. Here, we describe a tandem duplication of approximately 2 Mb at 7q34 occurring in 66% of PAs. This rearrangement, which was not observed in a series of 244 higher-grade astrocytomas, results in an in-frame fusion gene incorporating the kinase domain of the BRAF oncogene. We further show that the resulting fusion protein has constitutive BRAF kinase activity and is able to transform NIH3T3 cells. This is the first report of BRAF activation through rearrangement as a frequent feature in a sporadic tumor. The frequency and specificity of this change underline its potential both as a therapeutic target and as a diagnostic tool.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Duplicação Gênica , Fusão Gênica , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Células COS , Chlorocebus aethiops , Cromossomos Humanos Par 7 , Genes ras , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Análise de SobrevidaRESUMO
AIMS: Is glycaemic variability an independent risk factor for the development of microvascular complications in addition to average glycaemia, as assessed by glycated haemoglobin (HbA(1c))? In this study, an 11-year follow-up was carried out in patients with type 1 diabetes. The standard deviation of blood glucose (SDBG) concentration, an index of glycaemic variability, was calculated from self-monitored blood glucose data at baseline. METHODS: A total of 100 patients were randomly selected from 442 consecutive type 1 diabetic patients attending our outpatients clinic. SDBG was calculated from 70 measurements taken over a period of four weeks. Onset and progression of micro- and macrovascular complications were recorded over the 11-year follow-up. RESULTS: As expected, the prevalence of complications increased over time. Statistical analyses showed that HbA(1c) was an independent predictor of the incidence (P=0.004) and prevalence (P=0.01) of nephropathy. SDBG was found to be a predictor of the prevalence of peripheral neuropathy (P=0.03), and showed borderline significance in predicting the incidence of peripheral neuropathy (P=0.07). SDBG was also a highly significant predictor of hypoglycaemic unawareness (P=0.001). CONCLUSIONS: We conclude that variability of blood glucose may be important in the development of peripheral neuropathy in patients with type 1 diabetes, and that the nervous system may be particularly vulnerable to glycaemic variability.
Assuntos
Automonitorização da Glicemia/métodos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/complicações , Angiopatias Diabéticas/epidemiologia , Hemoglobinas Glicadas/análise , Adulto , Conscientização , Índice de Massa Corporal , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Angiopatias Diabéticas/sangue , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/epidemiologia , Retinopatia Diabética/sangue , Retinopatia Diabética/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , PrevalênciaRESUMO
The MDM2 gene is amplified and/or overexpressed in about 10% of glioblastomas and constitutes one of a number of ways the p53 pathway is disrupted in these tumours. MDM2 encodes a nuclear phosphoprotein that regulates several cell proteins by binding and/or ubiquitinating them, with p53 being a well-established partner. MDM2 has two promoters, P1 and P2 that give rise to transcripts with distinct 5' untranslated regions. Transcription from P2 is believed to be controlled by p53 and a single-nucleotide polymorphism (SNP309, T>G) in P2 is reported to be associated with increased risk for, and early development of, malignancies. The use of P1 and P2 has not been investigated in gliomas. We used RT-PCR to study P1- and P2-MDM2 transcript expression in astrocytic tumours, xenografts and cell lines with known MDM2, TP53 and p14(ARF) gene status. Both promoters were used in all genetic backgrounds including the use of the P2 promoter in TP53 null cells, indicating a p53-independent induction of transcription. Transcripts from the P1 promoter formed a greater proportion of the total MDM2 transcripts in tumours with MDM2 amplification, despite these tumours having two wild-type TP53 alleles. Examination of SNP309 in glioblastoma patients showed a borderline association with survival but no apparent correlation with age at diagnosis nor with TP53 and p14(ARF) status of their tumours. Our findings also indicate that elevated MDM2 mRNA levels in tumours with MDM2 amplification are preferentially driven by the P1 promoter and that the P2 promoter is not only regulated by p53 but also by other transcription factor(s).
Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/fisiologia , Adulto , Genótipo , Humanos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Astrocytic, oligodendroglial and mixed gliomas are the commonest gliomas in adults. They have distinct phenotypes and clinical courses, but as they exist as a continuous histological spectrum, differentiating them can be difficult. Co-deletions of total 1p and 19q are found in the majority of oligodendrogliomas and considered as a diagnostic marker and a prognostic indicator. The 1p status of astrocytomas has not yet been thoroughly examined. Using a chromosome 1 tile path array, we investigated 108 adult astrocytic tumours for copy number alterations. Total 1p deletions were rare (2%), however partial deletions involving 1p36 were frequently identified in anaplastic astrocytomas (22%) and glioblastomas (34%). Multivariate analysis showed that patients with total 1p deletions had significantly longer survival (P=0.005). In nine glioblastomas homozygous deletions at 1p36 were identified. No somatic mutations were found among the five genes located in the homozygously deleted region. However, the CpG island of TNFRSF9 was hypermethylated in 19% of astrocytic tumours and 87% of glioma cell lines. TNFRSF9 expression was upregulated after demethylation of glioma cell lines. Akt3 amplifications were found in four glioblastomas. Our results indicate that 1p deletions are common anaplastic astrocytomas and glioblastomas but are distinct from the 1p abnormalities in oligodendrogliomas.