Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Sci Rep ; 9(1): 10516, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324877

RESUMO

Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a "unique" CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.

2.
PLoS One ; 14(5): e0216472, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31095598

RESUMO

Comparative studies of colorectal cancer (CRC) according to the age of onset have found differences between early-onset CRC (EOCRC) and late-onset CRC (LOCRC). Using this as a starting point, we wished to determine whether intermediate-onset CRC (IOCRC) might also be considered as an independent group within CRC. We performed a retrospective comparative study of the clinicopathological and familial features, as well as of the symptoms and their duration, of a total of 272 subjects diagnosed with CRC classified into three groups according to the age-of-onset (98 EOCRC, 83 IOCRC and 91 LOCRC). The results show that from a clinicopathological point of view, IOCRC shared certain features with EOCRC (gender, prognosis), and with LOCRC (multiple primary CRCs), whereas it also had characteristics that were specific for IOCRC (mean number of associated polyps). A gradual progression was observed from EOCRC to LOCRC from a greater family aggregation to sporadic cases, in parallel with a change of Lynch Syndrome cases to the sporadic microsatellite instability pathway, with the IOCRC being a boundary group that is more related to EOCRC. With respect to symptoms, duration and correlation with stages, IOCRC appeared more similar to EOCRC. Clinically, IOCRC behaves as a transitional group between EOCRC and LOCRC, with features in common with both groups, but also with IOCRC-specific features. Excluding cases with familial cancer history, the awareness for EOCRC diagnosis should be extended to IOCRC.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Instabilidade de Microssatélites , Adulto , Idade de Início , Idoso , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
3.
Rev. neurol. (Ed. impr.) ; 68(7): 295-300, 1 abr., 2019. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-183314

RESUMO

Introducción. La amnesia aguda aislada es una forma excepcional de presentación del ictus talámico. Se analizan el perfil clínico, el diagnóstico, el tratamiento y el pronóstico de estos pacientes. Casos clínicos. Revisión retrospectiva de los casos de infarto talámico que se presentaron exclusivamente como amnesia aguda en nuestro hospital terciario universitario (n = 3) y revisión de casos similares en PubMed (n = 20). El 48% presentaba al menos un factor de riesgo de ictus (hipertensión arterial, dislipidemia, diabetes mellitus, fibrilación auricular o ictus previo). La amnesia fue anterógrada en tres casos (13%) y global en los otros 20 (87%). El infarto se detectó en estudio de neuroimagen en las primeras 24 horas en un paciente (4%) y posteriormente en los demás, y la media de días hasta el diagnóstico fue de 11. La tomografía computarizada inicial fue normal en cinco (22%) pacientes. Precisaron estudio por resonancia magnética ocho (35%) casos para detectar el infarto. De éstos, cuatro sujetos se estudiaron directamente con resonancia magnética. La amnesia presentó una mejoría clara en ocho (35%) pacientes, y la recuperación fue completa en tres (13%). Las secuelas mnésicas que interferían la capacidad funcional se presentaron en 15 pacientes (65%). La clínica persistió menos de 24 horas en dos pacientes (9%). Ningún caso recibió tratamiento revascularizador en fase aguda. Conclusión. Los infartos talámicos que comienzan de forma exclusiva con amnesia presentan notables dificultades diagnósticas que repercuten negativamente en su tratamiento en la fase aguda. Estos infartos pueden producir un déficit mnésico funcionalmente discapacitante en un porcentaje elevado de pacientes


Introduction. Isolated acute amnesia is an exceptional presenting symptom of thalamic stroke. This study analyses the clinical profile, the diagnosis, the treatment and the prognosis of these patients. Case reports. We conducted a retrospective review of the cases of thalamic infarct that presented exclusively as acute amnesia in our university tertiary hospital (n = 3) and a review of similar cases in PubMed (n = 20). 48% presented at least one risk factor of stroke (arterial hypertension, dyslipidaemia, diabetes mellitus, atrial fibrillation or a previous stroke). Amnesia was anterograde in three cases (13%) and global in the remaining 20 (87%). The infarct was detected in neuroimaging studies carried out within the first 24 hours in one patient (4%) and later in all the others; the average time until a diagnosis was established was 11 days. The initial CT scan was normal in five patients (22%). Eight cases (35%) required magnetic resonance imaging to detect the infarct. Of these, four subjects were studied directly with MR imaging. Amnesia clearly improved in eight patients (35%), and three of them (13%) made a full recovery. Fifteen patients (65%) presented mnemonic sequelae that interfered with their functional capacity. The clinical picture lasted less than 24 hours in two patients (9%). None of the cases received revasculisation therapy in the acute phase. Conclusion. The diagnosis of thalamic infarcts that begin exclusively with amnesia is very difficult and this has negative repercussions on their treatment in the acute phase. These infarcts can produce a functionally disabling memory deficit in a high percentage of patients


Assuntos
Humanos , Masculino , Idoso , Doenças Talâmicas/complicações , Doenças Talâmicas/diagnóstico , Infarto Cerebral/complicações , Infarto/diagnóstico por imagem , Amnésia/etiologia , Tomografia Computadorizada por Raios X , Imagem por Ressonância Magnética , Infarto/terapia , Doença Aguda , Prognóstico
4.
Int J Mol Sci ; 20(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813366

RESUMO

Our aim was to characterize and validate that the location and age of onset of the tumor are both important criteria to classify colorectal cancer (CRC). We analyzed clinical and molecular characteristics of early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and we compared each tumor location between both ages-of-onset. In right-sided colon tumors, early-onset cases showed extensive Lynch syndrome (LS) features, with a relatively low frequency of chromosomal instability (CIN), but a high CpG island methylation phenotype. Nevertheless, late-onset cases showed predominantly sporadic features and microsatellite instability cases due to BRAF mutations. In left colon cancers, the most reliable clinical features were the tendency to develop polyps as well as multiple primary CRC associated with the late-onset subset. Apart from the higher degree of CIN in left-sided early-onset cancers, differential copy number alterations were also observed. Differences among rectal cancers showed that early-onset rectal cancers were diagnosed at later stages, had less association with polyps, and more than half of them were associated with a familial LS component. Stratifying CRC according to both location and age-of-onset criteria is meaningful, not only because it correlates the resulting categories with certain molecular bases, but with the confirmation across larger studies, new therapeutical algorithms could be defined according to this subclassification.


Assuntos
Neoplasias Colorretais/classificação , Neoplasias Colorretais/patologia , Idade de Início , Neoplasias Colorretais/genética , Dosagem de Genes , Humanos
5.
Int J Cancer ; 144(7): 1596-1608, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30151896

RESUMO

To analyze the possible clonal origin of a part of Synchronous colorectal cancer (SCRC), we studied 104 paired-SCRCs from 52 consecutive patients without hereditary forms of CRC. We used a Single-Nucleotide Polymorphism array to characterize the genomic profiles, and subsequently used a statistical application to define them according to clonality within the same individual. We categorized the ensuing groups according to colonic location to identify differential phenotypes. The SCRC Monoclonal group (M) (19 cases) was divided into Monosegmental (MM) and Pancolonic (MP) groups. The SCRC Polyclonal group (P) (33 cases) was also divided into Monosegmental (PM) and Pancolonic (PP), the first exhibiting preference for left colon. The MM group showed a high rate of mucinous tumors, the lowest mean-number of tumors and associated-polyps, and the worst prognosis. The MP group included the largest mean-number of associated-polyps, best prognosis and familial cancer component. The PM group seemed to be a "frontier" group. Finally, the PP group also exhibited a mucin component, the highest mean-number of tumors (4.6) compared with the mean-number of polyps (7.7), poor prognosis and sporadic cases. Most relevant differential genomic regions within M groups were gains on 1q24 and 8q24, and deletions on 1p21 and 1p23 for MM, while within P were the gains on 7q36 and deletions on 1p36 for PM. The statistical application employed seems to define clonality more accurately in SCRC -more likely to be polyclonal in origin-, and together with the tumor locations, helped us to configure a classification with prognostic and clinical value.


Assuntos
Neoplasias Colorretais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Primárias Múltiplas/genética , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Idoso , Idoso de 80 Anos ou mais , Evolução Clonal , Neoplasias Colorretais/classificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/classificação , Prognóstico
6.
Clin Colorectal Cancer ; 16(1): 31-37, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27600984

RESUMO

BACKGROUND: Two or more primary colorectal tumors coexisting at the time of diagnosis are considered to be synchronous tumors. It is estimated that synchronous colorectal cancer (SCRC) only accounts for 1.1% to 8.1% of all colorectal cancers (CRCs), and its molecular basis is still poorly understood. PATIENTS AND METHODS: We evaluated the microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP) statuses in a series of 49 patients (98 tumors) diagnosed with sporadic SCRC at the 12 de Octubre University Hospital with the aim of improving the molecular characterization of this type of tumor. We considered Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis (MAP) as exclusion criteria. RESULTS: Molecular subgrouping on the basis of MSI and CIMP enabled us to define 4 groups that corresponded to the molecular classification proposed for single-tumor CRC. We observed a significant predominance of MSI tumors at the right side regardless of the methylation pattern, and a significant prevalence of microsatellite-stable tumors either at the left side or throughout the entire colon (P = .026). Furthermore, we defined some molecular features frequently observed in sporadic SCRC such as a low-frequency of MSI (8.2%). We observed a high concordance in terms of MSI between simultaneous tumors (93.9%) and a lower concordance in terms of CIMP (51%) between such tumors. CONCLUSION: Our findings support the hypothesis that SCRC involves an environmental rather than a genetic component in which various etiologic factors might modify tumor progression. Further studies are required to refine the molecular characterization of SCRC.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Instabilidade de Microssatélites , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino
7.
Neoplasia ; 19(1): 28-34, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27987438

RESUMO

AIM: To investigate whether chromosomal instability (CIN) is associated with tumor phenotypes and/or with global genomic status based on MSI (microsatellite instability) and CIMP (CpG island methylator phenotype) in early-onset colorectal cancer (EOCRC). METHODS: Taking as a starting point our previous work in which tumors from 60 EOCRC cases (≤45 years at the time of diagnosis) were analyzed by array comparative genomic hybridization (aCGH), in the present study we performed an unsupervised hierarchical clustering analysis of those aCGH data in order to unveil possible associations between the CIN profile and the clinical features of the tumors. In addition, we evaluated the MSI and the CIMP statuses of the samples with the aim of investigating a possible relationship between copy number alterations (CNAs) and the MSI/CIMP condition in EOCRC. RESULTS: Based on the similarity of the CNAs detected, the unsupervised analysis stratified samples into two main clusters (A, B) and four secondary clusters (A1, A2, B3, B4). The different subgroups showed a certain correspondence with the molecular classification of colorectal cancer (CRC), which enabled us to outline an algorithm to categorize tumors according to their CIMP status. Interestingly, each subcluster showed some distinctive clinicopathological features. But more interestingly, the CIN of each subcluster mainly affected particular chromosomes, allowing us to define chromosomal regions more specifically affected depending on the CIMP/MSI status of the samples. CONCLUSIONS: Our findings may provide a basis for a new form of classifying EOCRC according to the genomic status of the tumors.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Hibridização Genômica Comparativa , Estudos de Associação Genética , Predisposição Genética para Doença , Fenótipo , Adolescente , Adulto , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Aberrações Cromossômicas , Análise por Conglomerados , Neoplasias Colorretais/mortalidade , Ilhas de CpG , Metilação de DNA , Feminino , Instabilidade Genômica , Humanos , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Adulto Jovem
8.
Oncotarget ; 7(49): 80664-80679, 2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27811368

RESUMO

Multiple myeloma (MM) remains incurable despite the introduction of novel agents, and a relapsing course is observed in most patients. Although the development of genomic technologies has greatly improved our understanding of MM pathogenesis, the mechanisms underlying relapse have been less thoroughly investigated. In this study, an integrative analysis of DNA copy number, DNA methylation and gene expression was conducted in matched diagnosis and relapse samples from MM patients. Overall, the acquisition of abnormalities at relapse was much more frequent than the loss of lesions present at diagnosis, and DNA losses were significantly more frequent in relapse than in diagnosis samples. Interestingly, copy number abnormalities involving more than 100 Mb of DNA at relapse significantly affect the gene expression of these samples, provoking a particular deregulation of the IL-8 pathway. On the other hand, no significant modifications of gene expression were observed in those samples with less than 100 Mb affected by chromosomal changes. Although several statistical approaches were used to identify genes whose abnormal expression at relapse was regulated by methylation, only two genes that were significantly deregulated in relapse samples (SORL1 and GLT1D1) showed a negative correlation between methylation and expression. Further analysis revealed that DNA methylation was involved in regulating SORL1 expression in MM. Finally, relevant changes in gene expression observed in relapse samples, such us downregulation of CD27 and P2RY8, were most likely not preceded by alterations in the corresponding DNA. Taken together, these results suggest that the genomic heterogeneity described at diagnosis remains at relapse.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Metilação de DNA , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Integração de Sistemas , Linhagem Celular Tumoral , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Estudos de Associação Genética , Predisposição Genética para Doença , Glicosiltransferases/genética , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2Y/genética , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
9.
PLoS One ; 11(10): e0164370, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27741277

RESUMO

To explore novel genetic abnormalities occurring in myelodysplastic syndromes (MDS) through an integrative study combining array-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a series of MDS and MDS/myeloproliferative neoplasms (MPN) patients. 301 patients diagnosed with MDS (n = 240) or MDS/MPN (n = 61) were studied at the time of diagnosis. A genome-wide analysis of DNA copy number abnormalities was performed. In addition, a mutational analysis of DNMT3A, TET2, RUNX1, TP53 and BCOR genes was performed by NGS in selected cases. 285 abnormalities were identified in 71 patients (23.6%). Three high-risk MDS cases (1.2%) displayed chromothripsis involving exclusively chromosome 13 and affecting some cancer genes: FLT3, BRCA2 and RB1. All three cases carried TP53 mutations as revealed by NGS. Moreover, in the whole series, the integrative analysis of aCGH and NGS enabled the identification of cryptic recurrent deletions in 2p23.3 (DNMT3A; n = 2.8%), 4q24 (TET2; n = 10%) 17p13 (TP53; n = 8.5%), 21q22 (RUNX1; n = 7%), and Xp11.4 (BCOR; n = 2.8%), while mutations in the non-deleted allele where found only in DNMT3A (n = 1), TET2 (n = 3), and TP53 (n = 4). These cryptic abnormalities were detected mainly in patients with normal (45%) or non-informative (15%) karyotype by conventional cytogenetics, except for those with TP53 deletion and mutation (15%), which had a complex karyotype. In addition to well-known copy number defects, the presence of chromothripsis involving chromosome 13 was a novel recurrent change in high-risk MDS patients. Array CGH analysis revealed the presence of cryptic abnormalities in genomic regions where MDS-related genes, such as TET2, DNMT3A, RUNX1 and BCOR, are located.


Assuntos
Aberrações Cromossômicas , Síndromes Mielodisplásicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cromossomos Humanos Par 13 , Hibridização Genômica Comparativa , Subunidade alfa 2 de Fator de Ligação ao Core/genética , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Proteínas Proto-Oncogênicas/genética , Recidiva , Risco , Proteína Supressora de Tumor p53/genética , Adulto Jovem
10.
Mol Carcinog ; 55(5): 705-16, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-25808986

RESUMO

Chromosomal instability resulting in copy number alterations is a hallmark of colorectal cancer (CRC). However, few studies have attempted to characterize the chromosomal changes occurring in early-onset CRC in order to compare them with those taking place within the more extensively studied late-onset CRC subset. Our aim was to characterize the genomic profiles of these two groups of colorectal tumors and to compare them to each other. Array comparative genomic hybridization profiling of 146 colorectal tumors (60 early-onset and 86 late-onset) in combination with an unsupervised analysis was used to define common and specific copy number alterations. We found a number of important differences between the chromosomal instability profiles of each age subset. Thus, losses at 1p36, 1p12, 1q21, 9p13, 14q11, 16p13, and 16p12 were significantly more frequent in younger patients, whereas gains at 7q11 and 7q22 were more frequent in older patients. Moreover, the unsupervised analysis stratified the tumors into two clusters, each one of which was enriched in patients from one of the age subsets. Our findings confirm the existence of substantial differences between the chromosomal instability profiles of the two groups which are more important from a qualitative point of view. Further studies are needed to understand the clinicopathological implications of these dissimilarities.


Assuntos
Instabilidade Cromossômica , Neoplasias Colorretais/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Adulto Jovem
11.
Br J Haematol ; 172(3): 428-38, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26567765

RESUMO

The introduction of Rituximab has improved the outcome and survival rates of Burkitt lymphoma (BL). However, early relapse and refractoriness are current limitations of BL treatment and new biological factors affecting the outcome of these patients have not been explored. This study aimed to identify the presence of genomic changes that could predict the response to new therapies in BL. Forty adolescent and adult BL patients treated with the Dose-Intensive Chemotherapy Including Rituximab (Burkimab) protocol (Spanish Programme for the Study and Treatment of Haematological Malignancies; PETHEMA) were analysed using array-based comparative genomic hybridization (CGH). In addition, the presence of TP53, TCF3 (E2A), ID3 and GNA13 mutations was assessed by next-generation sequencing (NGS). Ninety-seven per cent of the patients harboured genomic imbalances. Losses on 11q, 13q, 15q or 17p were associated with a poor response to Burkimab therapy (P = 0·038), shorter progression-free survival (PFS; P = 0·007) and overall survival (OS; P = 0·009). The integrative analysis of array-CGH and NGS showed that 26·3% (5/19) and 36·8% (7/19) of patients carried alterations in the TP53 and TCF3 genes, respectively. TP53 alterations were associated with shorter PFS (P = 0·011) while TCF3 alterations were associated with shorter OS (P = 0·032). Genetic studies could be used for risk stratification of BL patients treated with the Burkimab protocol.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/genética , Aberrações Cromossômicas , Adolescente , Adulto , Idoso , Hibridização Genômica Comparativa/métodos , Feminino , Genoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Rituximab/administração & dosagem , Resultado do Tratamento , Adulto Jovem
12.
Am J Cancer Res ; 5(7): 2308-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26328262

RESUMO

Early-onset Colorectal Cancer (ECRC) represents a significant and increasing proportion of Colorectal Cancer (CRC), but it is a heterogeneous entity that probably encompasses specific subclasses. On the premise that the carcinogenetic mechanism and progression of CRC may differ with location, we analyzed molecular and clinical characteristics of ECRC according to tumor location in order to identify more homogeneous subgroups of CRC. Right-sided ECRC is a subset in which most Lynch Syndrome cases are found, with earlier stages at diagnosis and better prognosis. At this location the CpG Island Methylator Phenotype (CIMP) is predominant and Chromosomal Instability (CI) is rare. Left-sided ECRC appears as a transitional or intermediate location, except for CI tumors, that seem to predominate at this location. Finally, rectal ECRC shows Microsatellite Stability, CIMP low-0 and low CI - with recurrent altered chromosomal regions in common with left-sided ECRC-, possibly in relation with Microsatellite And Chromosomal Stable tumors, but with an unexpected familial component and worse prognosis. All this suggest that the molecular basis of ECRC varies with tumor location, which could affect the clinical management of patients.

13.
BMC Clin Pathol ; 13(1): 23, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24079673

RESUMO

BACKGROUND: Malignant astrocytomas are the most common primary brain tumors and one of the most lethal among human cancers despite optimal treatment. Therefore, the characterization of molecular alterations underlying the aggressive behavior of these tumors and the identification of new markers are thus an important step towards a better patient stratification and management. METHODS AND RESULTS: VRK1 and VRK2 (Vaccinia-related kinase-1, -2) expression, as well as proliferation markers, were determined in a tissue microarray containing 105 primary astrocytoma biopsies. Kaplan Meier and Cox models were used to find clinical and/or molecular parameters related to overall survival. The effects of VRK protein levels on proliferation were determined in astrocytoma cell lines. High levels of both protein kinases, VRK1 or VRK2, correlated with proliferation markers, p63 or ki67. There was no correlation with p53, reflecting the disruption of the VRK-p53-DRAM autoregulatory loop as a consequence of p53 mutations. High VRK2 protein levels identified a subgroup of astrocytomas that had a significant improvement in survival. The potential effect of VRK2 was studied by analyzing the growth characteristics of astrocytoma cell lines with different EGFR/VRK2 protein ratios. CONCLUSION: High levels of VRK2 resulted in a lower growth rate suggesting these cells are more indolent. In high-grade astrocytomas, VRK2 expression constitutes a good prognostic marker for patient survival.

14.
Am J Dermatopathol ; 35(3): e45-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23221470

RESUMO

Perineuriomas are benign neoplasms composed of perineurial cells. Classically, perineuriomas are divided into 2 distinct clinicopathologic entities, known as intraneural and extraneural perineuriomas. Intraneural perineuriomas, first described as interstitial hypertrophic neuritis, involve the major nerve trunks, causing motor or sensory deficits. Here, we report a case of a 42-year-old man presenting a lesion on the second finger of the right hand. The patient did not refer any previous trauma, tenderness, or sensorial nerve deficit. Histologic analysis showed a plexiform dermal lesion composed of enlarged nerve fascicles due to proliferation of spindle perineurial cells, arranged in onion-bulb-like structures. The proliferating cells showed positive membranous staining for epithelial membrane antigen and were negative for S100 protein, which highlighted residual Schwann cells. Fluorescence in situ hybridization studies revealed the loss of one signal for chromosome 22 probe in 15% of the spindle cells. In our report, we present the first case of cutaneous intraneural perineurioma, a benign tumor, which expands the morphological spectrum of cutaneous neural lesions.


Assuntos
Neoplasias da Bainha Neural/patologia , Neoplasias Cutâneas/patologia , Adulto , Biomarcadores Tumorais/análise , Biópsia , Proliferação de Células , Cromossomos Humanos Par 22 , Dedos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Mucina-1/análise , Neoplasias da Bainha Neural/química , Neoplasias da Bainha Neural/genética , Valor Preditivo dos Testes , Proteínas S100/análise , Neoplasias Cutâneas/química , Neoplasias Cutâneas/genética
15.
Int J Hematol ; 96(3): 320-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22806436

RESUMO

Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, persistent hypereosinophilia associated with multiple organ dysfunctions. The cause of HES is unknown and shows clinical heterogeneity. FIP1L1-PDGFRA fusion is a clonal marker for the diagnosis and treatment of HES. We prospectively studied 78 patients with chronic eosinophilia. In all cases, the most salient clinical and biological characteristics as well as the response to the therapy were analyzed. In addition, we performed conventional cytogenetics and fluorescent in situ hybridization (FISH) with three BACs covering the FIP1-like-1 (FIP1L1)/platelet-derived growth factor receptor-α gene (PDGFRA) fusion. Nineteen of 78 patients (24 %) presented criteria of HES. The majority of patients were male (18) with median age of 49 years (range 19-84 years). FIP1L1-PDGFRA fusion was found in eight patients. Patients with FIP1L1-PDGFRA fusion presented with more bone marrow eosinophils and peripheral blood eosinophilia as well as anemia, leukocytosis and thrombocytopenia. Using of low-dose imatinib mesylate (100 mg/day) a hematological and molecular remission in all patients displaying the FIP1L1-PDGFRA fusion gene was observed. Therefore, imatinib may be effective for use in the treatment of chronic eosinophilic leukemia, and patients should be treated before tissue damage.


Assuntos
Antineoplásicos/uso terapêutico , Síndrome Hipereosinofílica/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Benzamidas , Aberrações Cromossômicas , Feminino , Humanos , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/genética , Mesilato de Imatinib , Cariótipo , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Resultado do Tratamento , Adulto Jovem , Fatores de Poliadenilação e Clivagem de mRNA/genética
16.
Eur J Haematol ; 89(1): 37-41, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22587685

RESUMO

OBJECTIVES: The myeloproliferative neoplasms displaying a PDGFRB rearrangement are rare diseases derived from a haematopoietic stem cell. The goals of the study were to assess the incidence of these disorders and to define the clinical and biological characteristics as well as the response to the imatinib therapy. METHODS: A total of 556 patients with myeloproliferative neoplasms were studied by means of molecular cytogenetics. RESULTS: The incidence of myeloproliferative neoplasms (MPN) with PDGFRB rearrangement was low (10 cases, 1.8% of all MPN). Most of the patients showed moderate anaemia (median Hb was 10.0 gr/dL; range from 7.5 to 13 g/dL), leukocytosis (median white blood cells was 21.7 × 10(9) /L with a range from 4 to 43 × 10(9) /L) and eosinophilia (median circulating eosinophils was 2.4 × 10(9) /L with a range of 1.1-5.7 × 10(9) /L) with a median of bone marrow infiltration cells displaying PDGFRB rearrangement of 55% (range, 37-85%). In three cases, a t(5;12) was observed while two patients showed rearrangements of 17q21 region. In two cases, a del(5)(q31) was observed. Most of the patients responded to standard dosage of imatinib, and the response was maintained in the time in those patients with a follow-up higher than 9 years. CONCLUSIONS: The incidence of patients with PDGFRB rearrangement is low. These patients showed leukocytosis with eosinophilia and anaemia. The efficacy of imatinib therapy in patients showing PDGFRB rearrangement is high. For this reason, in all patients with MPN without any other molecular aberration, PDGFRB rearrangement should be ascertained.


Assuntos
Neoplasias da Medula Óssea/epidemiologia , Neoplasias da Medula Óssea/genética , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Benzamidas , Neoplasias da Medula Óssea/tratamento farmacológico , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Incidência , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/tratamento farmacológico , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Resultado do Tratamento
17.
Pharmacogenet Genomics ; 22(5): 381-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22388797

RESUMO

BACKGROUND: Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. It is well known that CML cells are genetically unstable. However, the mechanisms by which these cells acquire genetic alterations are poorly understood. Imatinib mesylate is the standard therapy for newly diagnosed CML patients. Imatinib mesylate targets the oncogenic kinase activity of BCR-ABL. OBJECTIVE: To study the gene expression profile of bone marrow hematopoietic cells in the same patients with CML before and 1 month after imatinib therapy. METHODS: Samples from patients with CML were analyzed using Affymetrix GeneChip Expression Arrays. RESULTS: A total of 594 differentially expressed genes, most of which (393 genes) were downregulated, as a result of imatinib therapy were observed. CONCLUSION: The blockade of oncoprotein Bcr-Abl by imatinib could cause a decrease in the expression of key DNA repair genes and substantially modify the expression profile of the bone marrow cells in the first days of therapy.


Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Benzamidas , Células da Medula Óssea/metabolismo , Proteínas de Ciclo Celular/genética , Dano ao DNA/genética , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Proteínas de Fusão bcr-abl/genética , Perfilação da Expressão Gênica , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade
18.
Ann Surg Oncol ; 19(7): 2367-79, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22395973

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults. Patients with GBM have few treatment options, and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment; however, the use of these will require a fuller understanding of the genetic changes in this complex tumor. METHODS: We analyzed a series of 32 patients with GBM with array comparative genomic hybridization in combination with gene expression analysis. We focused on the recurrent breakpoints found by spectral karyotyping (SKY). RESULTS: By SKY we identified 23 recurrent breakpoints of the 202 translocations found in GBM cases. Gains and losses were identified in chromosomal regions close to the breakpoints by array comparative genomic hybridization. We evaluated the genes located in the regions involved in the breakpoints in depth. A list of 406 genes that showed a level of expression significantly different between patients and control subjects was selected to determine their effect on survival. Genes CACNA2D3, PPP2R2B, SIK, MAST3, PROM1, and PPP6C were significantly associated with shorter survival (median 200 days vs. 450 days, P≤0.03). CONCLUSIONS: We present a list of genes located in regions of breakpoints that could be grounds for future studies to determine whether they are crucial in the pathogenesis of this type of tumor, and we provide a list of six genes associated with the clinical outcome of patients with GBM.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Cariotipagem Espectral , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Glioblastoma/mortalidade , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida
19.
PLoS One ; 6(9): e24939, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21957467

RESUMO

Splenic marginal zone lymphomas (SMZL) are an uncommon type of B-cell non-Hodgkin's lymphoma (NHL-B) in which no specific chromosomal translocations have been described. In contrast, the most frequent cytogenetic abnormality is the loss of the long arm of chromosome 7 (7q). Previous reports have located this loss in the 7q32 region. In order to better characterize the genomic imbalances in SMZL, molecular studies were carried out in 73 patients with SMZL. To gain insight into the mapping at 7q a tiling array was also used. The results confirmed the loss of 7q as the most frequent change. In addition, several abnormalities, including 4q22.1, 1q21.3-q22, 6q25.3, 20q13.33, 3q28, 2q23.3-q24.1 and 17p13, were also present. A loss of 7q22.1 at 99925039-101348479 bp was observed in half of the cases. The region of 7q22.1 has not previously been characterised in SMZL. Our results confirmed the presence of a new region of loss on chromosome 7 in these NHL.


Assuntos
Cromossomos Humanos Par 7/genética , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Deleção Cromossômica , Cromossomos Artificiais Bacterianos/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes
20.
BMC Cancer ; 10: 454, 2010 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-20735813

RESUMO

BACKGROUND: Gliomas are the most common type of primary brain tumours, and in this group glioblastomas (GBMs) are the higher-grade gliomas with fast progression and unfortunate prognosis. Two major aspects of glioma biology that contributes to its awful prognosis are the formation of new blood vessels through the process of angiogenesis and the invasion of glioma cells. Despite of advances, two-year survival for GBM patients with optimal therapy is less than 30%. Even in those patients with low-grade gliomas, that imply a moderately good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells with characteristics of neural stem cells which are able to grow in vitro forming neurospheres and that can be isolated in vivo using surface markers such as CD133. The aim of this study was to define the molecular signature of GBM cells expressing CD133 in comparison with non expressing CD133 cells. This molecular classification could lead to the finding of new potential therapeutic targets for the rationale treatment of high grade GBM. METHODS: Eight fresh, primary and non cultured GBMs were used in order to study the gene expression signatures from its CD133 positive and negative populations isolated by FACS-sorting. Dataset was generated with Affymetrix U133 Plus 2 arrays and analysed using the software of the Affymetrix Expression Console. In addition, genomic analysis of these tumours was carried out by CGH arrays, FISH studies and MLPA; RESULTS: Gene expression analysis of CD133+ vs. CD133- cell population from each tumour showed that CD133+ cells presented common characteristics in all glioblastoma samples (up-regulation of genes involved in angiogenesis, permeability and down-regulation of genes implicated in cell assembly, neural cell organization and neurological disorders). Furthermore, unsupervised clustering of gene expression led us to distinguish between two groups of samples: those discriminated by tumour location and, the most importantly, the group discriminated by their proliferative potential; CONCLUSIONS: Primary glioblastomas could be sub-classified according to the properties of their CD133+ cells. The molecular characterization of these potential stem cell populations could be critical to find new therapeutic targets and to develop an effective therapy for these tumours with very dismal prognosis.


Assuntos
Antígenos CD/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Glicoproteínas/genética , Peptídeos/genética , Antígeno AC133 , Idoso , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Hibridização Genômica Comparativa , Feminino , Citometria de Fluxo , Glioblastoma/metabolismo , Glicoproteínas/metabolismo , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Peptídeos/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA