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2.
Sci Rep ; 9(1): 14991, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628391

RESUMO

Breast cancer in very young women (≤35 years; BCVY) presents more aggressive and complex biological features than their older counterparts (BCO). Our aim was to evaluate methylation differences between BCVY and BCO and their DNA epigenetic age. EPIC and 450k Illumina methylation arrays were used in 67 breast cancer tumours, including 32 from BCVY, for methylation study and additionally we analysed their epigenetic age. We identified 2 219 CpG sites differently-methylated in BCVY vs. BCO (FDR < 0.05; ß-value difference ± 0.1). The signature showed a general hypomethylation profile with a selective small hypermethylation profile located in open-sea regions in BCVY against BCO and normal tissue. Strikingly, BCVY presented a significant increased epigenetic age-acceleration compared with older women. The affected genes were enriched for pathways in neuronal-system pathways, cell communication, and matrix organisation. Validation in an independent sample highlighted consistent higher expression of HOXD9, and PCDH10 genes in BCVY. Regions implicated in the hypermethylation profile were involved in Notch signalling pathways, the immune system or DNA repair. We further validated HDAC5 expression in BCVY. We have identified a DNA methylation signature that is specific to BCVY and have shown that epigenetic age-acceleration is increased in BCVY.

3.
ESMO Open ; 4(3): e000470, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231566

RESUMO

Background: The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors. Material and methods: We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation. Results: Forty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable tumour-specific survival (TSS) in stages I-III (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04). Conclusions: The MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.

4.
Cancer Med ; 8(6): 3120-3130, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31059199

RESUMO

Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions. Thirty-six patients diagnosed with advanced colorectal cancer from two referent public hospitals from Paraguay were recruited from May 2017 to February 2018. Sequenom Mass spectrometry, Oncocarta Panel V.1 was applied to analyze the mutational profile from formalin-fixed paraffin-embedded samples. The microsatellite status was tested by immunohistochemistry (IHC). The mean age of the patients was 52 years with a range from 20 to 74 years. Eighty-three percent of the patients included in the study have advanced-stage tumors at the moment of the diagnosis. Sixteen patients (44.4%) were wild-type for all the oncogene regions analyzed with the Oncocarta panel. Thirty-two hot-spot pathogenic variants on seven oncogenes, among 20 patients (55.6%), were identified, including KRAS, NRAS, BRAF, PI3KCA, FGFR, epidermal growth factor receptor, and PDGFRA. Moreover, 14 (38.8%) of these patients presented pathogenic variants in KRAS/NRAS or BRAF genes that have implications in the clinical practice decisions. Five patients (14%) presented MSI. The IHC study for microsatellite status and the molecular profile analysis through Sequenom mass spectrometry are feasible and useful methods, due to identify those patient candidates for targeted therapies and for the budgetary calculations of the National Health Plans.

5.
Lancet Child Adolesc Health ; 3(5): 332-342, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872112

RESUMO

BACKGROUND: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. METHODS: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. FINDINGS: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. INTERPRETATION: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. FUNDING: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.


Assuntos
Biomarcadores Tumorais/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Receptor Tipo 1 de Melanocortina/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , Estudos Retrospectivos
6.
Breast Cancer (Auckl) ; 13: 1178223419828766, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814839

RESUMO

Purpose: Breast cancer (BC) in very young women (BCVY) is more aggressive than in older women. The purpose of this study was to evaluate the relevance of a range of clinico-pathological factors in the prognosis of BCVY patients. Methods: We retrospectively analyzed 258 patients diagnosed with BCVY at our hospital from 1998 to 2014; the control group comprised 101 older patients with BC. We correlated clinicopathological factors, treatments, relapse and exitus with age and with previously published miRNA expression data. Results: We identified some significant differences in risk factors between BCVY and older patients. The age at menarche, number of pregnancies, and age at first pregnancy were lower in the BCVY group and had a greater probability of recurrence and death in all cases. Lymph node-positive patients in the BCVY group are associated with a worse prognosis (P = .02), an immunohistochemical HER2+ subtype, and disease relapse (P = .03). Moreover, there was a shorter time between diagnosis and first relapse in BCVY patients compared with controls, and they were more likely to die from the disease (P = .002). Finally, from our panel of miRNAs deregulated in BC, reduced miR-30c expression was associated with more aggressive BC in very young patients, lower overall survival, and with axillary lymph node metastases. Conclusions: Patient age and axillary lymph node status post-surgery are independent and significant predictors of distant disease-free survival, local recurrence-free survival, and overall survival. The HER2+ subtype and lower miR-30c expression are related to poor prognosis in lymph node-positive young BC patients.

7.
Mod Pathol ; 32(2): 306-313, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30206410

RESUMO

At the histological level, tumor budding in colon cancer is the result of cells undergoing at least partial epithelial-to-mesenchymal transition. The microRNA 200 family is an important epigenetic driver of this process, mainly by downregulating zinc-finger E-box binding homeobox (ZEB) and transforming growth factor beta (TGF-ß) expression. We retrospectively explored the expression of the miR200 family, and ZEB1 and ZEB2, and their relationship with immune resistance mediated through PD-L1 overexpression. For this purpose, we analyzed a series of 125 colon cancer cases and took samples from two different tumor sites: the area of tumor budding at the invasive front and from the tumor center. We found significant ZEB overexpression and a reduction in miR200 in budding areas, a profile compatible with epithelial-to-mesenchymal transition. In multivariate analysis of the cases with localized disease, low miR200c expression in budding areas, but not at the tumor center, was an adverse tumor-specific survival factor (hazard ratio: 0.12; 95% confidence interval: 0.03-0.81; p = 0.02) independent of the clinical stage of the disease. PD-L1 was significantly overexpressed in the budding areas and its levels correlated with a mesenchymal transition profile. These results highlight the importance of including budding areas among the samples used for biomarker evaluation and provides relevant data on the influence of mesenchymal transition in the immune resistance mediated by PD-L1 overexpression.


Assuntos
Antígeno B7-H1/biossíntese , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal/genética , MicroRNAs/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
Rev. psiquiatr. salud ment. (Barc., Ed. impr.) ; 11(4): 227-233, oct.-dic. 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-176756

RESUMO

Introducción: La vigilancia y prevención de la conducta suicida requiere, entre otros datos, conocer con precisión las muertes por suicidio (MPS). Frecuentemente existe una infradeclaración o mala clasificación de las MPS en las estadísticas oficiales de mortalidad. El objetivo del estudio es analizar la infradeclaración de la estadística de mortalidad por suicidio en Tarragona (Cataluña, España). Material y métodos: Análisis de las MPS ocurridas en la División de Tarragona del Institut de Medicina Legal i Ciències Forenses de Catalunya (DT-IMLCFC) entre los años 2004 y 2012. Las fuentes de información fueron el fichero de defunciones del Registre de Mortalitat de Catalunya (RMC) y el archivo de autopsias del DT-IMLCFC. Se compararon estadísticamente las tasas y las características demográficas de las MPS declaradas en el RMC y las recuperadas. Resultados: La media de casos no declarados en el período fue del 16,2%, con el mínimo en el año 2005 (2,2%) y el máximo en el año 2009 (26,8%). La tasa bruta de mortalidad por suicidio pasó de 6,6 por 100.000 habitantes a 7,9 por 100.000 habitantes tras la incorporación de los datos forenses. Se detectaron diferencias poco importantes en el perfil sociodemográfico de los suicidios declarados inicialmente y los definitivos, excepto en el método de suicidio, con un aumento significativo de los envenenamientos y los arrollamientos en vía férrea. Conclusiones: La recuperación de datos en las MPS a partir de las fuentes forenses mejora la información estadística, corrigiendo su infradeclaración y ampliando el conocimiento sobre el método de suicidio y las características personales


Introduction: Monitoring and preventing suicidal behaviour requires, among other data, knowing suicide deaths precisely. They often appear under-reported or misclassified in the official mortality statistics. The aim of this study is to analyse the under-reporting found in the suicide mortality statistics of Tarragona (a province of Catalonia, Spain). Method and materials: The analysis takes into account all suicide deaths that occurred in the Tarragona Area of the Catalan Institute of Legal Medicine and Forensic Sciences (TA-CILMFS) between 2004 and 2012. The sources of information were the death data files of the Catalan Mortality Register, as well as the Autopsies Files of the TA-CILMFS. Suicide rates and socio-demographic profiles were statistically compared between the suicide initially reported and the final one. Results: The mean percentage of non-reported cases in the period was 16.2%, with a minimum percentage of 2.2% in 2005 and a maximum of 26.8% in 2009. The crude mortality rate by suicide rose from 6.6 to 7.9 per 100,000 inhabitants once forensic data were incorporated. Small differences were detected between the socio-demographic profile of the suicide initially reported and the final one. Supplementary information was obtained on the suicide method, which revealed a significant increase in poisoning and suicides involving trains. Conclusions: An exhaustive review of suicide deaths data from forensic sources has led to an improvement in the under-reported statistical information. It also improves the knowledge of the method of suicide and personal characteristics


Assuntos
Humanos , Suicídio/estatística & dados numéricos , Tentativa de Suicídio/estatística & dados numéricos , Registros de Mortalidade/estatística & dados numéricos , Causas de Morte , Psiquiatria Legal/estatística & dados numéricos , Notificação , Estatísticas Vitais
9.
Sci Rep ; 8(1): 14373, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258192

RESUMO

MiRNAs are part of the epigenetic machinery, and are also epigenetically modified by DNA methylation. MiRNAs regulate expression of different genes, so any alteration in their methylation status may affect their expression. We aimed to identify methylation differences in miRNA encoding genes in breast cancer affecting women under 35 years old (BCVY), in order to identify potential biomarkers in these patients. In Illumina Infinium MethylationEPIC BeadChip samples (metEPICVal), we analysed the methylation of 9,961 CpG site regulators of miRNA-encoding genes present in the array. We identified 193 differentially methylated CpG sites in BCVY (p-value < 0.05 and methylation differences ±0.1) that regulated 83 unique miRNA encoding genes. We validated 10 CpG sites using two independent datasets based on Infinium Human Methylation 450k array. We tested gene expression of miRNAs with differential methylation in BCVY in a meta-analysis using The Cancer Genome Atlas (TCGA), Clariom D and Affymetrix datasets. Five miRNAs (miR-9, miR-124-2, miR-184, miR-551b and miR-196a-1) were differently expressed (FDR p-value < 0.01). Finally, only miR-124-2 shows a significantly different gene expression by quantitative real-time PCR. MiR-124-hypomethylation presents significantly better survival rates for older patients as opposed to the worse prognosis observed in BCVY, identifying it as a potential specific survival biomarker in BCVY.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Regiões Promotoras Genéticas , Adulto , Fatores Etários , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Ilhas de CpG , Feminino , Humanos , Prognóstico , Análise de Sobrevida
10.
Rev Psiquiatr Salud Ment ; 11(4): 227-233, 2018.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-27450705

RESUMO

INTRODUCTION: Monitoring and preventing suicidal behaviour requires, among other data, knowing suicide deaths precisely. They often appear under-reported or misclassified in the official mortality statistics. The aim of this study is to analyse the under-reporting found in the suicide mortality statistics of Tarragona (a province of Catalonia, Spain). METHOD AND MATERIALS: The analysis takes into account all suicide deaths that occurred in the Tarragona Area of the Catalan Institute of Legal Medicine and Forensic Sciences (TA-CILMFS) between 2004 and 2012. The sources of information were the death data files of the Catalan Mortality Register, as well as the Autopsies Files of the TA-CILMFS. Suicide rates and socio-demographic profiles were statistically compared between the suicide initially reported and the final one. RESULTS: The mean percentage of non-reported cases in the period was 16.2%, with a minimum percentage of 2.2% in 2005 and a maximum of 26.8% in 2009. The crude mortality rate by suicide rose from 6.6 to 7.9 per 100,000 inhabitants once forensic data were incorporated. Small differences were detected between the socio-demographic profile of the suicide initially reported and the final one. Supplementary information was obtained on the suicide method, which revealed a significant increase in poisoning and suicides involving trains. CONCLUSIONS: An exhaustive review of suicide deaths data from forensic sources has led to an improvement in the under-reported statistical information. It also improves the knowledge of the method of suicide and personal characteristics.


Assuntos
Causas de Morte , Confiabilidade dos Dados , Melhoria de Qualidade , Suicídio/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Espanha/epidemiologia , Suicídio/prevenção & controle
11.
Exp Dermatol ; 26(10): 896-903, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28266728

RESUMO

Sunlight exposure induces signalling pathways leading to the activation of melanin synthesis and tanning response. MicroRNAs (miRNAs) can regulate the expression of genes involved in pigmentation pathways by binding to the complementary sequence in their 3'untranslated regions (3'UTRs). Therefore, 3'UTR SNPs are predicted to modify the ability of miRNAs to target genes, resulting in differential gene expression. In this study, we investigated the role in pigmentation and sun-sensitivity traits, as well as in melanoma susceptibility, of 38 different 3'UTR SNPs from 38 pigmentation-related genes. A total of 869 individuals of Spanish origin (526 melanoma cases and 343 controls) were analysed. The association of genotypic data with pigmentation traits was analysed via logistic regression. Web-based tools for predicting the effect of genetic variants in microRNA-binding sites in 3'UTR gene regions were also used. Seven 3'UTR SNPs showed a potential implication in melanoma risk phenotypes. This association is especially noticeable for two of them, rs2325813 in the MLPH gene and rs752107 in the WNT3A gene. These two SNPs were predicted to disrupt a miRNA-binding site and to impact on miRNA-mRNA interaction. To our knowledge, this is the first time that these two 3'UTR SNPs have been associated with sun-sensitivity traits. We state the potential implication of these SNPs in human pigmentation and sensitivity to sunlight, possibly as a result of changes in the level of gene expression through the disruption of putative miRNA-binding sites.


Assuntos
Regiões 3' não Traduzidas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Melanoma/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/genética , Pigmentação da Pele/genética , Proteína Wnt3A/genética , Sítios de Ligação , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Cor de Olho/genética , Frequência do Gene , Predisposição Genética para Doença , Cor de Cabelo/genética , Humanos , Lentigo/genética , MicroRNAs/genética , Fenótipo , Transtornos de Fotossensibilidade/genética , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , RNA Mensageiro/genética , Fatores de Risco , Espanha
13.
Breast Cancer Res Treat ; 160(1): 69-77, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27628192

RESUMO

BACKGROUND: There is increasing interest in the molecular profiling of tumour tissues in order to investigate alternative breast cancer (BC) therapies. However, the impact of genomic screening for druggable mutations with targeted gene panel sequencing (TGPS) in routine practice remains controversial. METHODS: This is a retrospective analysis of data from a genomic screening programme at our institution, in which we performed simplified TGPS for mutations in PIK3CA, AKT1, KRAS, NRAS, and BRAF in order to select patients for targeted therapy clinical trials. The genomes of archived samples of primary (PT) and/or metastatic (MT) tumours from advanced BC patients were analysed with MassARRAY technology (Sequenom MassARRAY, OncoCarta v1.0). The level of PTEN expression was assessed by immunohistochemistry. The primary endpoint was to identify the proportion of BC patients with PI3 K and MAPK alterations who were included in clinical trials using targeted therapies against these pathways. RESULTS: Two hundred and fifteen metastatic BC patients (65 PT and 168 MT) were included. Fifty-two patients (24.19 %) were enrolled in tailored clinical trials, of whom 29 (55.77, 13.49 % of all patients screened) harboured mutations targeted by the study drug. Moreover, 12 wild-type patients out of the 215 (5.58 %) were included in the clinical trials for which mutation analysis was an inclusion criteria. All the patients received drugs targeting the PI3K-AKT pathway and only two were given combinations directed against the PI3K and MAPK pathways. PI3KCA mutations were present in 33.7 % (61/181) of the patients, 45.83 % in PTs and 29.32 % in MTs. AKT1 mutations were detected in 5.48 % (8/146) of patients and PTEN loss in 34.67 % (52/150). KRAS, NRAS, and BRAF mutations were present in 12.06, 5.67, and 3.18 % of patients, respectively. CONCLUSIONS: Genomic screening with a simplified TGPS is feasible, and was used to identify 13.49 % of patients who were included in clinical trials using targeted therapy against the mutations they harboured; PI3KCA mutations were the most frequent aberration in our series.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Mutação , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genômica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias
14.
Cancer Treat Rev ; 49: 57-64, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27501018

RESUMO

This article will review the impact of the recently developed MassARRAY technology on our understanding of cancer biology and treatment. Analysis of somatic mutations is a useful tool in selecting personalized therapy, and for predicting the outcome of many solid tumors. Here, we review the literature on the application of MassARRAY technology (Sequenom Hamburg, Germany) to determine the mutation profile of solid tumors from patients. We summarize the use of commercially available panels of mutations - such as OncoCarta™ or other combinations - and their concordance with results obtained by using other technologies, such as next generation sequencing.


Assuntos
Neoplasias/genética , Oncogenes/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Medicina de Precisão
15.
Oncotarget ; 7(39): 63424-63436, 2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27566570

RESUMO

Gastric cancer (GC) pathogenesis involves genetic, epigenetic and environmental factors. Epigenetic alterations, such as DNA methylation are considered pivotal in the inactivation of tumor-related genes. We assessed a methylation panel of 5 genes to study their association to GC progression and microsatellite instability (MSI), and studied the role of RUNX3 in GC pathogenesis and the tumor immune microenvironment.The methylation status of 47 promoter-CpG islands was studied through MALDI-TOF mass spectrometry analysis in 35 Microsatellite stable (MSS) GC, 26 MSI, and 18 cancer-free samples (CFS), and 6 MSS GC and 4 MSI GC cell lines. We also studied RUNX3 expression by immunohistochemistry (IHC) in 40 samples, and validated differences in methylation levels between tumor, normal, and immune tissue in 14 additional samples.Unsupervised hierarchical clustering of methylation levels revealed no distinct subgroups between MSI and MSS samples or cell lines. CFSs clustered together showing higher levels of RUNX3 methylation compared to GC samples. RUNX3 showed protein silencing in cancer and normal mucosa, compared to inflammatory peritumoural infiltrate in almost all cases, showing a non-lymphocytic predominant pattern and being correlated with epigenetic silencing.Our results show aberrant promoter's methylation in APC, CDH1, CDKN2A, MLH1 and RUNX3 associated with GC, as well as a non-lymphocytic predominant infiltrate with high expression of RUNX3. Deep study of RUNX3 inflammation signaling could help in understanding inflammation and immune activation in the tumor microenvironment.


Assuntos
Biomarcadores Tumorais/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Metilação de DNA , Epigênese Genética , Neoplasias Gástricas/genética , Microambiente Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Ilhas de CpG , Feminino , Seguimentos , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Taxa de Sobrevida
17.
Oncotarget ; 7(16): 22543-55, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26968814

RESUMO

Somatic mutation analysis represents a useful tool in selecting personalized therapy. The aim of our study was to determine the presence of common genetic events affecting actionable oncogenes using a MassARRAY technology in patients with advanced solid tumors who were potential candidates for target-based therapies. The analysis of 238 mutations across 19 oncogenes was performed in 197 formalin-fixed paraffin-embedded samples of different tumors using the OncoCarta Panel v1.0 (Sequenom Hamburg, Germany). Of the 197 specimens, 97 (49.2%) presented at least one mutation. Forty-nine different oncogenic mutations in 16 genes were detected. Mutations in KRAS and PIK3CA were detected in 40/97 (41.2%) and 30/97 (30.9%) patients respectively. Thirty-one patients (32.0%) had mutations in two genes, 20 of them (64.5%) initially diagnosed with colorectal cancer. The co-occurrence of mutation involved mainly KRAS, PIK3CA, KIT and RET. Mutation profiles were validated using a customized panel and the Junior Next-Generation Sequencing technology (GS-Junior 454, Roche). Twenty-eight patients participated in early clinical trials or received specific treatments according to the molecular characterization (28.0%). MassARRAY technology is a rapid and effective method for identifying key cancer-driving mutations across a large number of samples, which allows for a more appropriate selection for personalized therapies.


Assuntos
Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Medicina de Precisão/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Biol Sex Differ ; 7: 17, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26998216

RESUMO

BACKGROUND: Human pigmentation is a polygenic quantitative trait with high heritability. In addition to genetic factors, it has been shown that pigmentation can be modulated by oestrogens and androgens via up- or down-regulation of melanin synthesis. Our aim was to identify possible sex differences in pigmentation phenotype as well as in melanoma association in a melanoma case-control population of Spanish origin. METHODS: Five hundred and ninety-nine females (316 melanoma cases and 283 controls) and 458 males (234 melanoma cases and 224 controls) were analysed. We genotyped 363 polymorphisms (single nucleotide polymorphisms (SNPs)) from 65 pigmentation gene regions. RESULTS: When samples were stratified by sex, we observed more SNPs associated with dark pigmentation and good sun tolerance in females than in males (107 versus 75; P = 2.32 × 10(-6)), who were instead associated with light pigmentation and poor sun tolerance. Furthermore, six SNPs in TYR, SILV/CDK2, GPR143, and F2RL1 showed strong differences in melanoma risk by sex (P < 0.01). CONCLUSIONS: We demonstrate that these genetic variants are important for pigmentation as well as for melanoma risk, and also provide suggestive evidence for potential differences in genetic effects by sex.

19.
Oncotarget ; 6(29): 26935-45, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26334097

RESUMO

Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10-5) and 73.8% (P = 1.00 × 10-3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10-6), miR-19a-3p (P = 1.23 × 10-4), miR-128-3p (P = 3.49 × 10-4), miR-130b-3p (P = 1.00 × 10-3) and miR-34a-5p (P = 4.00 × 10-3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy.


Assuntos
Caderinas/metabolismo , MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Neoplasias Gástricas/genética , Fatores de Transcrição/metabolismo , Idoso , Antígenos CD , Biomarcadores Tumorais , Cromatina/química , Classe I de Fosfatidilinositol 3-Quinases , Epigênese Genética , Feminino , Mucosa Gástrica/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/metabolismo
20.
IUBMB Life ; 67(4): 227-38, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25904072

RESUMO

Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGFß), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may yield novel therapeutic targets or prognostic markers for breast cancer.


Assuntos
Neoplasias da Mama/patologia , Lactação , Glândulas Mamárias Humanas/fisiopatologia , Feminino , Humanos , NF-kappa B/metabolismo , Peptídeo Hidrolases/metabolismo , Gravidez , Fatores de Risco , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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