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2.
Mod Pathol ; 30(2): 169-179, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27739437

RESUMO

In this study, we investigate in detail the morphological, clinical and molecular features of 71 consecutive patients with a diagnosis of myeloproliferative neoplasms, unclassifiable. We performed a meticulous morphological analysis and found that most of the cases displayed a hypercellular bone marrow (70%) with normal erythropoiesis without left-shifting (59%), increased granulopoiesis with left-shifting (73%) and increased megakaryocytes with loose clustering (96%). Megakaryocytes displayed frequent giant forms with hyperlobulated or bulbous nuclei and/or other maturation defects. Interestingly, more than half of the cases displayed severe bone marrow fibrosis (59%). Median values of hemoglobin level and white blood cells count were all within the normal range; in contrast, median platelets count and lactate dehydrogenase were increased. Little less than half of the patients (44%) showed splenomegaly. JAK2V617F mutation was detected in 72% of all patients. Among the JAK2-negative cases, MPLW515L mutation was found in 17% and CALR mutations in 67% of the investigated cases, respectively. Finally, by multiple correspondence analysis of the morphological profiles, we found that all but four of the cases could be grouped in three morphological clusters with some features similar to those of the classic BCR-ABL1-negative myeloproliferative neoplasms. Analysis of the clinical parameters in these three clusters revealed discrepancies with the morphological profile in about 55% of the patients. In conclusion, we found that the category of myeloproliferative neoplasm, unclassifiable is heterogeneous but identification of different subgroups is possible and should be recommended for a better management of these patients.


Assuntos
Medula Óssea/patologia , Mutação , Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Calbindina 2/genética , Feminino , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Mielofibrose Primária/genética , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Receptores de Trombopoetina/genética , Adulto Jovem
3.
Histopathology ; 70(6): 1000-1008, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28074480

RESUMO

AIMS: The aims of this study were to define whether diffuse cutaneous reticulohistiocytosis could be underpinned by somatic genetic alterations and represent a precursor of more aggressive forms of disease. METHODS AND RESULTS: A 59-year-old man with diffuse cutaneous reticulohistiocytosis experienced bone marrow localization of the disease, with associated systemic mastocytosis and acute myeloid leukaemia. Cytogenetic analyses of the bone marrow aspirate revealed the presence of a derivative chromosome giving rise to a partial trisomy of chromosome 1q and a partial monosomy of chromosome 9q. Therefore, we characterized the cutaneous lesions before and after chemotherapy by using an integrative approach combining histopathology, electron microscopy, and fluorescence in-situ hybridization. Histologically, the skin lesions belonged to the spectrum of diffuse cutaneous reticulohistiocytoses, as confirmed by immunohistochemistry and ultrastructural analyses. Fluorescence in-situ hybridization in the skin nodules confirmed the presence of the genetic alterations previously detected in the bone marrow. CONCLUSIONS: Here, we provide circumstantial evidence to suggest that at least a subset of cutaneous reticulohistiocytoses harbour clonal molecular alterations. Furthermore, we confirm that these lesions have the potential to arise in the setting of concurrent haematological disorders. In this hypothesis-generating study, two possible tumorigenesis models are proposed.


Assuntos
Neoplasias da Medula Óssea/complicações , Transtornos Histiocíticos Malignos/complicações , Leucemia Mieloide Aguda/complicações , Mastocitose Sistêmica/complicações , Neoplasias Cutâneas/complicações , Medula Óssea/patologia , Neoplasias da Medula Óssea/genética , Neoplasias da Medula Óssea/patologia , Células Clonais/patologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
4.
Histopathology ; 70(6): 906-917, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28072477

RESUMO

AIMS: Pulmonary adenofibromas are rare benign fibroepithelial tumours of the lung with unknown histogenesis and an indolent clinical behaviour. Their stroma resembles that of solitary fibrous tumours, whereas the glands are composed of respiratory epithelium organized in a phyllodes-like architecture. Differentiation of pulmonary adenofibromas from other more aggressive intrathoracic tumours is clinically relevant. However, their biology is unknown. Here, we sought to characterize pulmonary adenofibromas at a clinicopathological level and to define whether they could be underpinned by a highly recurrent somatic genetic alteration akin to tumours with similar morphology. METHODS AND RESULTS: Seven pulmonary adenofibromas were subjected to immunohistochemical analysis for thyroid transcription factor 1 (TTF1), napsin A, cytokeratin 7, E-cadherin, CD99, CD34, CD31, STAT6, oestrogen receptor (ER), progesterone receptor, androgen receptor, bcl-2, and vimentin, as well as electron microscopy and capillary sequencing on microdissected samples to evaluate the presence of NAB2-STAT6 fusion genes and MED12 exon 2 mutations in their discrete components. A control group comprising pulmonary solitary fibrous tumours, pulmonary hamartomas and breast fibroadenomas was also analysed. We confirmed that the stromal elements of pulmonary adenofibromas pertain to the fibroblastic lineage, and show ER overexpression in 71% of cases, whereas the epithelium consists of TTF1-positive, E-cadherin positive bronchiolar elements. A highly recurrent NAB2-STAT6 fusion variant (exon 4-exon 2) was detected in the stroma but not in the epithelium. No MED12 mutations were identified. CONCLUSIONS: Here, we demonstrate that pulmonary adenofibromas are neoplastic lesions harbouring the molecular hallmark of solitary fibrous tumours.


Assuntos
Adenofibroma/genética , Receptor alfa de Estrogênio/biossíntese , Neoplasias Pulmonares/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT6/genética , Adenofibroma/metabolismo , Adenofibroma/patologia , Idoso , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Microdissecção e Captura a Laser , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética
5.
Ann Hematol ; 95(12): 1965-1969, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27595148

RESUMO

Morbidity and mortality of BCR-ABL1-negative myeloproliferative neoplasm (MPN) patients are influenced by disease-related hemostatic complications, mostly of thrombotic nature. The pathogenesis of thrombosis is multifactorial: in particular, it has been demonstrated that a deregulated expression of Mac1 (also known as surface receptor integrin CD18/CD11b) by leukocytes has a role in favoring platelets' activation in MPN patients. Based on these data, we investigated the epigenetic status of CD18/CD11b in 78 primary myelofibrosis (PMF) patients to explore any possible association between the epigenetic profiles of these two genes and thrombotic risk. The percentage of CD18 methylation in the PMF samples ranged from hypomethylated to hypermethylated (range: 11-90 %, mean: 64 %), whereas in controls CD18 methylation status clustered in a more restricted interval (range: 24-68 %, mean: 45 %; cases vs. CONTROLS: p = 0.006). Furthermore, the results showed that CD18 hypermethylation (>76 % methylation) was correlated with thrombotic complications. On the contrary, CD11b promoter resulted unmethylated (1-5 %) in both cases and controls. Previous studies showed that older age, JAK2V617F mutation, and thrombophilia might play a role in MPN patients' thrombotic risk. In our cases, the prognostic value of these variables was coherent, being thrombotic events significantly associated with age >65 years (p = 0.001), JAK2 mutation (p = 0.01), and positive thrombophilia tests (p = 0.04). However, multivariate analysis showed that only CD18 methylation and age >65 years were independent prognostic factors of thrombosis (p = 0.02 and p = 0.04, respectively). Taken together, our findings suggest a possible role of CD18 epigenetic regulation in the pathogenesis of the thrombotic complications in PMF patients.


Assuntos
Antígenos CD18/genética , Metilação de DNA/genética , Mielofibrose Primária/genética , Regiões Promotoras Genéticas/genética , Trombose/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/complicações , Mielofibrose Primária/diagnóstico , Fatores de Risco , Trombose/diagnóstico , Trombose/etiologia , Adulto Jovem
6.
Liver Int ; 35(3): 1077-86, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25040368

RESUMO

BACKGROUND & AIMS: Sorafenib is the standard of care in advanced hepatocellular carcinoma (HCC), however no criteria have been established to select patients likely to benefit from this therapy. In this study, we evaluated the predictive role of microRNAs (miRNAs) in this setting of patients. METHODS: We profiled 522 miRNA in a series of 26 HCC patients treated with sorafenib (training set) and validated the results in an independent series of 58 patients (validation set). Formalin-fixed paraffin-embedded tumour and cirrhotic liver biopsies were used for RNA extraction and miRNAs profiling with TaqMan Arrays technology. Statistical analyses were used to correlate miRNA levels with clinical outcome, including time to progression (TTP), progression free (PFS), and overall survival. Cell viability and cell motility of HuH-7 or HepG2 HCC cells were tested in vitro after transfection with specific miRNA precursor, inhibitor or controls and sorafenib treatment. RESULTS: Six miRNAs were significantly associated with clinical variables in the training set and only miR-425-3p could be further validated. Higher levels of miR-425-3p were associated with longer TTP and PFS (P = 0.0008; HR = 0.4; 95% CI = 0.2-0.7 and P = 0.007; HR = 0.5; 95% CI = 0.3-0.9 respectively). Multivariate analysis confirmed the predictive significance of miR-425-3p. Furthermore, an association between increased miR-425-3p, cell death and reduced cell motility was defined in vitro in HCC cell lines treated with sorafenib. CONCLUSIONS: Assessment of miR-425-3p levels in liver biopsies could help in stratifying patients with advanced HCC for sorafenib treatment. These promising results need to be confirmed in a large prospective study.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Niacinamida/uso terapêutico , Sorafenibe
7.
Liver Int ; 32(5): 772-82, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22429613

RESUMO

BACKGROUND AND AIMS: Progressive hepatocarcinogenesis is a stepwise process that drives liver transformation. However, the molecular mechanisms of early liver transformation are far from clear. A role for microRNAs (miRNA) as diagnostic and prognostic factors in human tumours, including hepatocellular carcinoma (HCC), is promising. We aimed to identify novel miRNA as biomarkers for differential diagnosis and predictors of disease progression. METHODS: We used a low-density array platform to profile the expression of 664 mature miRNA in a cohort of 60 hepatitis C virus-positive liver lesions representative of all stages of progressive hepatocarcinogenesis. We validated selected miRNA in two independent patient series by qPCR and we characterized the genomic status of the miRNA cluster C19MC by fluorescent in situ hybridization and copy-number variation analyses. RESULTS: A 18-miRNA signature distinguished cirrhosis, dysplastic nodules and HCC lesions. Four miRNAs overexpressed in HCCs belonged to chromosome 19 miRNA cluster (C19MC). Significant overexpression of C19MC in early HCC compared to dysplastic nodules could be confirmed in a second series of hepatitis B virus-related liver lesions (n = 30). In a third series of 61 HCCs, C19MC cluster was overexpressed in HCCs compared to matched cirrhotic parenchyma and regardless of the type of viral infection. High C19MC miRNA levels were correlated with poor clinico-pathological features, increased risk of tumour recurrence and shorter overall survival time. HCCs overexpressing the C19MC cluster showed genetic amplification of the corresponding locus. CONCLUSIONS: C19MC cluster is a novel molecular alteration characteristic of liver cancer and predictor of poor prognosis. C19MC is an attractive candidate for novel HCC therapies.


Assuntos
Apoptose/genética , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Marcação de Genes , Neoplasias Hepáticas/patologia , MicroRNAs/fisiologia , Via de Sinalização Wnt/genética , Feminino , Humanos , Masculino
10.
BMC Cancer ; 9: 125, 2009 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-19397802

RESUMO

BACKGROUND: Similarly to other tumor types, an imbalance between unrestrained cell proliferation and impaired apoptosis appears to be a major unfavorable feature of hepatocellular carcinoma (HCC). The members of IAP family are key regulators of apoptosis, cytokinesis and signal transduction. IAP survival action is antagonized by specific binding of Smac/DIABLO and XAF1. This study aimed to investigate the gene and protein expression pattern of IAP family members and their antagonists in a series of human HCCs and to assess their clinical significance. METHODS: Relative quantification of IAPs and their antagonist genes was assessed by quantitative Real Time RT-PCR (qPCR) in 80 patients who underwent surgical resection for HCC. The expression ratios of XIAP/XAF1 and of XIAP/Smac were also evaluated. Survivin, XIAP and XAF1 protein expression were investigated by immunohistochemistry. Correlations between mRNA levels, protein expression and clinicopathological features were assessed. Follow-up data were available for 69 HCC patients. The overall survival analysis was estimated according to the Kaplan-Meier method. RESULTS: Survivin and Livin/ML-IAP mRNAs were significantly over-expressed in cancer tissues compared to non-neoplastic counterparts. Although Survivin immunoreactivity did not correlate with qPCR data, a significant relation was found between higher Survivin mRNA level and tumor stage, tumor grade and vascular invasion.The mRNA ratio XIAP/XAF1 was significantly higher in HCCs than in cirrhotic tissues. Moreover, high XIAP/XAF1 ratio was an indicator of poor prognosis when overall survival was estimated and elevated XIAP immunoreactivity was significantly associated with shorter survival. CONCLUSION: Our study demonstrates that alterations in the expression of IAP family members, including Survivin and Livin/ML-IAP, are frequent in HCCs. Of interest, we could determine that an imbalance in XIAP/XAF1 mRNA expression levels correlated to overall patient survival, and that high XIAP immunoreactivity was a poor prognostic factor.


Assuntos
Carcinoma Hepatocelular/patologia , Proteínas Inibidoras de Apoptose/genética , Neoplasias Hepáticas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Apoptose , Proteínas Reguladoras de Apoptose , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Distribuição de Qui-Quadrado , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Survivina , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
11.
Dig Liver Dis ; 50(6): 583-593, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29673952

RESUMO

BACKGROUND: Intratumor heterogeneity of hepatocellular carcinoma (HCC) and, among HCC cell subsets, the cancer stem cell population (hCSC), is responsible for therapeutic resistance and disease relapse. AIMS: To characterize hCSC-enriched HCCs at the molecular level. METHODS: Side population (SP) was used to identify the hCSCs in multiple tumor sampling from different patients and primary HCCs cultures. FACS was used to immunoprofile cultures. miRNAs were profiled in samples and correlated to SP. The Cancer Genome Atlas (TCGA) HCC dataset was analyzed to search for signatures associated with C19MC miRNAs expression. Results were confirmed by immunohistochemistry. RESULTS: The miRNA cluster on chromosome 19 (C19MC) was enriched in SP and in HCCs with a high SP fraction. At the molecular level, an elevated C19MC was correlated with expression of precursor transcripts. In TCGA-HCC series, high C19MC expression identified a subset of patients with poorer prognosis, advanced disease and overexpression of the cancer-testis (CT) antigens. These data were confirmed in an independent cohort of HCCs and at the protein level. CONCLUSION: C19MC miRNAs and CT antigens overexpression represents a novel oncogenic pathway in a subset of hCSC-enriched HCCs with dismal prognosis. CT antigens are promising immunotherapy targets. Therefore, these molecular signatures could identify HCCs who could benefit from immunotherapy.


Assuntos
Carcinoma Hepatocelular/patologia , Cromossomos Humanos Par 19/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Células-Tronco Neoplásicas/citologia , Animais , Antígenos de Neoplasias/genética , Carcinogênese/genética , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Transplante de Neoplasias , Células da Side Population/citologia
12.
Oncotarget ; 8(5): 7231-7247, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-27980227

RESUMO

Lung cancer is the leading cause of tumor-related death worldwide and more efforts are needed to elucidate lung carcinogenesis. Here we investigated the expression of 641 miRNAs in lung tumorigenesis in a K-Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model and 113 human tumors. The conserved miRNA cluster on chromosome 12qF1 was significantly and progressively upregulated during murine lung carcinogenesis. In particular, miR-494-3p expression was correlated with lung cancer progression in mice and with worse survival in lung cancer patients. Mechanistically, ectopic expression of miR-494-3p in A549 lung cancer cells boosted the tumor-initiating population, enhanced cancer cell motility, and increased the expression of stem cell-related genes. Importantly, miR-494-3p improved the ability of A549 cells to grow and metastasize in vivo, modulating NOTCH1 and PTEN/PI3K/AKT signaling.Overall, these data identify miR-494-3p as a key factor in lung cancer onset and progression and possible therapeutic target.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Células A549 , Animais , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genes ras , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos Nus , Camundongos Transgênicos , MicroRNAs/metabolismo , Mutação , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Células da Side Population/metabolismo , Células da Side Population/patologia , Transdução de Sinais , Fatores de Tempo , Transfecção , Carga Tumoral
13.
Epigenomics ; 8(3): 341-58, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26949823

RESUMO

BACKGROUND: Tumor epigenetic defects are of increasing relevance to clinical practice, because they are 'druggable' targets for cancer therapy using chromatin-remodeling agents (CRAs). New evidences highlight the importance of the microenvironment on the epigenome regulation and the need to use culture models able to preserve tissue morphology, to better understand the action of CRAs. Methods & methods: We studied the epigenetic response induced by culturing and CRAs in a preclinical model, preserving ex vivo the original tissue microenvironment and morphology, assessing different epigenetic signatures. Our overall findings suggest that culturing and CRAs cause heterogeneous effects on the genes methylation; CRAs affect the global DNA methylation and can trigger an active DNA demethylation; the culture induces alterations in the histone deacetylase expression. CONCLUSION: Despite the limited number of cases, these findings can be considered a proof of concept of the possibility to test CRAs epigenetic effects on ex vivo tissues maintained in their native tissue architecture.


Assuntos
Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Epigênese Genética , Neoplasias Pulmonares/genética , Pulmão/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/secundário , Epigênese Genética/efeitos dos fármacos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Elementos Nucleotídeos Longos e Dispersos/genética , Pulmão/citologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Regiões Promotoras Genéticas , Microambiente Tumoral
14.
J Neuropathol Exp Neurol ; 75(8): 791-800, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27346749

RESUMO

Several molecular markers drive diagnostic classification, prognostic stratification, and/or prediction of response to therapy in patients with gliomas. Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene. However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus. Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype. We also explored a potential association between MGMT methylation and loss of chromosome 10q. We observed that MGMT methylation was heterogeneously distributed within glioma samples irrespective of IDH status suggesting an incomplete overlap between IDH1-mutated and MGMT-methylated alleles and indicating a partial association between these two events. Moreover, loss of one MGMT allele did not affect the methylation level of the remaining allele. MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.

15.
Leuk Res ; 39(5): 525-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25840747

RESUMO

We examined a consecutive series of 29 patients with myeloproliferative neoplasms (MPNs) associated with splanchnic vein thrombosis (SVT) in order to evaluate their bone marrow morphology and identify possible associations between histological findings and clinical features. Eleven patients showed the morphological features of polycythemia vera (PV), 11 of primary myelofibrosis (PMF) and six of essential thrombocythemia (ET). Molecular analyses identified the JAK2 V617F mutation in 27 patients; one of the JAK2-negative patients carried the MPL W515K mutation, the other was "triple-negative" (no JAK2, MPL or CALR mutation). On the basis of the WHO classification, three patients were classified as having PV, 11 as having PMF, and two as having ET; the remaining 13 cases fell into the MPN-unclassifiable category as there were discrepancies between their morphological and clinical features. In conclusion, our findings suggest that bone marrow histology should always be considered a key component of the diagnostic algorithm in patients with SVT, but that it is not enough to distinguish the different entities. This is particularly important because diagnoses of PV, PMF or ET have very different prognoses and obviously imply different therapies. It is therefore necessary to adopt a comprehensive approach that considers morphological, clinical and molecular data.


Assuntos
Medula Óssea/patologia , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/patologia , Trombose Venosa/complicações , Trombose Venosa/patologia , Adolescente , Adulto , Idoso , Síndrome de Budd-Chiari/complicações , Síndrome de Budd-Chiari/epidemiologia , Síndrome de Budd-Chiari/patologia , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Masculino , Isquemia Mesentérica/complicações , Isquemia Mesentérica/epidemiologia , Isquemia Mesentérica/patologia , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Fenótipo , Veia Porta/patologia , Estudos Retrospectivos , Circulação Esplâncnica , Veia Esplênica/patologia , Trombose Venosa/epidemiologia , Adulto Jovem
16.
Leuk Res ; 39(2): 236-41, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25498506

RESUMO

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterised by the clonal proliferation of the haematopoietic precursors together with the progressive development of bone marrow fibrosis. This stromal alteration is an important clinical issue and specific prognostic markers are not currently available. In bone marrow biopsies from 58 PMF patients, we explored the methylation pattern of genes encoding cytokines involved in the stromal reaction, namely platelet-derived growth factor-beta (PDGFB), transforming growth factor-beta (TGFB) and basic fibroblast growth factor (FGF2). We also evaluated the methylation profile of the Long Interspersed Nucleotide Element 1 (LINE-1). PDGFB, FGF2 and LINE-1, but not TGFB, were significantly differently methylated in PMF compared to controls. Significantly, PDGFB hypomethylation (<16%) was correlated with a favourable PMF prognosis (grade of marrow fibrosis, p=0.03; International Prognostic Scoring Systems p=0.01 and Dynamic International Prognostic Scoring Systems, p=0.02). Although the basis of the association of PDGFB hypomethylation with favourable prognosis remains to be clarified, we speculate that hypomethylation in PMF could represent the effect of acquired somatic mutations in genes involved in epigenetic regulation of the genome.


Assuntos
Metilação de DNA , Epigênese Genética , Mielofibrose Primária/metabolismo , Proteínas Proto-Oncogênicas c-sis/biossíntese , Biomarcadores/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/biossíntese , Fator 2 de Crescimento de Fibroblastos/genética , Humanos , Elementos Nucleotídeos Longos e Dispersos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/genética , Prognóstico , Proteínas Proto-Oncogênicas c-sis/genética , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genética
17.
J Clin Pathol ; 67(8): 697-701, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24914240

RESUMO

AIMS: To identify molecular characteristics to hepatitis C virus (HCV)-associated diffuse large B-cell lymphoma (DLBCL) through a comprehensive miRNAs expression profiling. METHODS: In this study, miRNA profiles were obtained from 37 patients with DLBCLs and 60 patients with reactive lymph nodes, equally distributed according to HCV presence. Germinal centres, from reactive lymph nodes were used as controls. Clinical features at presentation were available for all patients. RESULTS: A set of 52 miRNAs define a signature for HCV-associated DLBCL. Importantly, decreased expression of miR-138-5p and increased expression of miR-147a, miR-147b and miR-511-5p in HCV DLBCL was found to be a poor prognostic factor for HCV-positive DLBCL patients. CONCLUSIONS: These data reveal molecular differences in diffuse DLBCL patients according to HCV presence, potentially useful as novel prognostic or therapeutic biomarkers.


Assuntos
Hepacivirus , Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico
18.
Epigenetics ; 8(10): 1053-60, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23917791

RESUMO

Beckwith-Wiedemann syndrome (BWS) is a rare disorder characterized by overgrowth and predisposition to embryonal tumors. BWS is caused by various epigenetic and/or genetic alterations that dysregulate the imprinted genes on chromosome region 11p15.5. Molecular analysis is required to reinforce the clinical diagnosis of BWS and to identify BWS patients with cancer susceptibility. This is particularly crucial prenatally because most signs of BWS cannot be recognized in utero. We established a reliable molecular assay by pyrosequencing to quantitatively evaluate the methylation profiles of ICR1 and ICR2. We explored epigenotype-phenotype correlations in 19 patients that fulfilled the clinical diagnostic criteria for BWS, 22 patients with suspected BWS, and three fetuses with omphalocele. Abnormal methylation was observed in one prenatal case and 19 postnatal cases, including seven suspected BWS. Seven cases showed ICR1 hypermethylation, five cases showed ICR2 hypomethylation, and eight cases showed abnormal methylation of ICR1 and ICR2 indicating paternal uniparental disomy (UPD). More cases of ICR1 alterations and UPD were found than expected. This is likely due to the sensitivity of this approach, which can detect slight deviations in methylation from normal levels. There was a significant correlation (p<0.001) between the percentage of ICR1 methylation and BWS features: severe hypermethylation (range: 75-86%) was associated with macroglossia, macrosomia, and visceromegaly, whereas mild hypermethylation (range: 55-59%) was associated with umbilical hernia and diastasis recti. Evaluation of ICR1 and ICR2 methylation by pyrosequencing in BWS can improve epigenotype-phenotype correlations, detection of methylation alterations in suspected cases, and identification of UPD.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Metilação de DNA , Epigênese Genética , Criança , Pré-Escolar , Feminino , Doenças Fetais/genética , Impressão Genômica , Hérnia Umbilical/genética , Humanos , Lactente , Masculino , Fenótipo
19.
Breast Cancer Res Treat ; 105(3): 267-76, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17221156

RESUMO

PURPOSE: To evaluate the contribution of germline BRCA1 mutations in the incidence of hereditary and familial Breast Cancer (BC) and/or Ovarian Cancer (OC) in patients from Southern Italy (in the region of Sicily) and to identify a possible association between the higher frequency of BRCA1 mutations and a specific familial profile. EXPERIMENTAL DESIGN: A consecutive series of 650 patients with BC and/or OC diagnosed between 1999 and 2005 were recruited from the Southern Italian region of Sicily, after interview at the "Regional Reference Centre for the Characterization and Genetic Screening of Hereditary Tumors" at the University of Palermo. Genetic counselling allowed us to recruit a total of 106 unrelated families affected with breast and/or ovarian cancer screened for mutations occurring in the whole BRCA1 gene by automatic direct sequencing. RESULTS: Germline BRCA1 mutations were found in 17 of 106 (16%) Sicilian families. The HBOC profile had a major frequency (66%) of mutations (P < 0.01). A total of 28 sequence variants was identified. Seven of these were pathogenic, 5 unknown biological variant (UV) and 16 polymorphisms. We also identified a pathological mutation (4843delC) as a possible Sicilian founder mutation. CONCLUSIONS: The present study is the first BRCA1 disease-associated mutations analysis in Southern Italian families. The early age of onset of such tumors and the association with the HBOC familial profile could be two valid screening factors for the identification of BRCA1 mutation carriers. Finally, we identified a BRCA1 mutation with a possible founder effect.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Sequência de Bases , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença/epidemiologia , Testes Genéticos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Linhagem , Polimorfismo Genético
20.
Breast Cancer Res Treat ; 96(1): 97-100, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16244786

RESUMO

A group of 103 sicilian patients with hereditary and familiar breast and/or ovarian cancer were screened for Breast Cancer 1 gene (BRCA1) mutations by direct sequencing PCR products spanning the coding region and partial intronic regions of the BRCA1 gene. In this study, we report a new germline mutation in BRCA1 gene, not previously reported in the BIC database, in a woman with ovarian cancer at 46 years old. Mother's proband has been diagnosed the same histotype of ovarian cancer at 42 age. The mutational analyses that shown a 4843delC frameshift mutation in exon 16 of BRCA1 gene was extended to other family members including the proband's brother and her two sons. Direct automatic sequencing of DNA extracted from the lymphocytes showed exactly the same 4843delC frameshift mutation only in the brother. In conclusion, the characterization of this mutation could help in the identification of a founder mutation of sicilian area and this may provide significant advantages for genetic counselling.


Assuntos
Cistadenocarcinoma/genética , Genes BRCA1/fisiologia , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Adulto , Feminino , Mutação da Fase de Leitura/genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Sicília/epidemiologia
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