RESUMO
Sex differences in the prevalence of psychiatric disorders are well documented, with exposure to stress during gestation differentially impacting females and males. We explored sex-specific DNA methylation in the cord blood of 39 females and 32 males born at term and with appropriate weight at birth regarding their potential connection to psychiatric outcomes. Mothers were interviewed to gather information about environmental factors (gestational exposure) that could interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. Excluding XYS probes, there were 2,332 differentially methylated CpG sites (DMSs) between sexes, which were enriched within brain modules of co-methylated CpGs during brain development and also differentially methylated in the brains of boys and girls. Genes associated with the DMSs were enriched for neurodevelopmental disorders, particularly for CpG sites found differentially methylated in brain tissue between patients with schizophrenia and controls. Moreover, the DMS had an overlap of 890 (38%) CpG sites with a cohort submitted to toxic exposition during gestation. This study supports the evidences that sex differences in DNA methylation of autosomes act as a primary driver of sex differences that are found in psychiatric outcomes.
Assuntos
Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Esquizofrenia/genética , Adulto , Ilhas de CpG/genética , Feminino , Sangue Fetal/metabolismo , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/fisiopatologia , Esquizofrenia/sangue , Esquizofrenia/fisiopatologia , Caracteres Sexuais , Sexismo/psicologiaRESUMO
O câncer de mama (BC) em mulheres jovens tem um comportamento biológico mais agressivo e está associado a um pior prognóstico em comparação com BC ocorridos em pacientes mais velhas. Estudos publicados anteriormente sugerem que essa característica agressiva do BC em pacientes adultas jovens (AJ) parece apresentar características biológicas particulares, enquanto que outros autores consideram a representação dos subtipos agressivos. A influência de fatores genéticos pode contribuir para o mau prognóstico de BC em jovens adultas com 35 anos ou menos. No entanto, mutação nos genes BRCA1/2 não poderia explicar a maioria dos casos de AJ. Os microRNAs (miRs) têm sido explorados nos aspectos genéticos de BC. O objetivo do nosso trabalho foi identificar a diferença nos perfis de expressão de miRs e seus alvos (mRNAs e proteínas) entre tumores esporádicos de pacientes adultas jovens com menos de 35 anos (grupo AJ) e pacientes de meia idade com 50 a 65 anos (gropo MI), não-portadores de mutação nos genes BRCA1 / 2. Cinquenta pacientes brasileiras com carcinoma ductal invasivo de mama foram classificados com um fenótipo luminal. Mas características agressivas foram mais evidentes em tumores AJ, tais como maior tamanho do tumor e grau histológico avançado em comparação com tumores do MI. Usando o método de qPCR identificamos 8 miRs diferencialmente expressos em tumores do AJ em relação ao MI, com mais de 90% de confiança. A super expressão de miR-9, 33b 210, e baixa expressão de miR-372 foram correlacionados com tumores com características patológicas agressivas e a baixa expressão de miR-210 106b, 518a-3p foram associados com menor tamanho do tumor e TNM menos avançado...
Breast cancer (BC) in young patients has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in older patients. Previously published studies suggested that BC in young adult (YA-BC) patients appears to present distinct biological features, others considered over representation of aggressive subtypes underlined these tumor characteristics. The influence of genetic factors may contribute to the poor prognosis of BC at young adult aged 35 years or less. However, BRCA1/2 mutations could not explain the majority of cases arising in these patients. MicroRNAs (miRs) have been implicated in genetic aspects of BC. Using miRs, mRNA and protein expression profiles the aim of our study was to identify differentially expression profiles between sporadic tumors from young patients (under 35 years) and patients aged 50 to 65 years, non-carriers of BRCA1/2 mutations. Fifty Brazilian patients were divided into 2 groups: young adults patients with less than 35 years (YA-BC) or meddle age patients with 50 to 65 yeasrs (MABC) with invasive ductal breast carcinoma. All tumors were classified as presenting a luminal phenotype but aggressive characteristics were more evident in YA-BC tumors such as larger tumor size and advanced histological grade which were statistically significant different (P<0.05) than in MA-BC tumors...
Assuntos
Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Neoplasias da Mama , Carcinoma Ductal de Mama , Biomarcadores Tumorais , Carcinoma , Expressão Gênica , MicroRNAsRESUMO
The influence of genetic factors may contribute to the poor prognosis of breast cancer (BC) at a very young age. However BRCA1/2 mutations could not explain the majority of cases arising in these patients. MicroRNAs (miRs) have been implicated in biological processes associated with BC. Therefore, we investigated differences in miRs expression between tumors from young patients (≤35 years) with sporadic or familial history and non-carriers of BRCA1/2 mutations. Thirty-six young Brazilian patients were divided into 2 groups: sporadic (NF-BC) or familial breast cancer (F-BC). Most of the samples were classified as luminal A and B and the frequency of subtypes did not differ between familial or sporadic cases. Using real time qPCR and discriminant function analysis, we identified 9 miRs whose expression levels rather than miR identity can discriminate between both patient groups. Candidate predicted targets were determined by combining results from miRWalk algorithms with mRNA expression profiles (nâ=â91 differently expressed genes). MiR/mRNA integrated analysis identified 91 candidate genes showing positive or negative correlation to at least 1 of the 9 miRs. Co-expression analysis of these genes with 9 miRs indicated that 49 differentially co-expressed miR-gene interactions changes in F-BC tumors as compared to those of NF-BC tumors. Out of 49, 17 (34.6%) of predicted miR-gene interactions showed an inverse correlation suggesting that miRs act as post-transcriptional regulators, whereas 14 (28.6%) miR-gene pairs tended to be co-expressed in the same direction indicating that the effects exerted by these miRs pointed to a complex level of target regulation. The remaining 18 pairs were not predicted by our criteria suggesting involvement of other regulators. MiR-mRNA co-expression analysis allowed us to identify changes in the miR-mRNA regulation that were able to distinguish tumors from familial and sporadic young BC patients non-carriers of BRCA mutations.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/metabolismo , MicroRNAs/metabolismo , Adulto , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , MicroRNAs/genética , Transcriptoma , Adulto JovemRESUMO
The importance of epithelial-stroma interaction in normal breast development and tumor progression has been recognized. To identify genes that were regulated by these reciprocal interactions, we cocultured a nonmalignant (MCF10A) and a breast cancer derived (MDA-MB231) basal cell lines, with fibroblasts isolated from breast benign-disease adjacent tissues (NAF) or with carcinoma-associated fibroblasts (CAF), in a transwell system. Gene expression profiles of each coculture pair were compared with the correspondent monocultures, using a customized microarray. Contrariwise to large alterations in epithelial cells genomic profiles, fibroblasts were less affected. In MDA-MB231 highly represented genes downregulated by CAF derived factors coded for proteins important for the specificity of vectorial transport between ER and golgi, possibly affecting cell polarity whereas the response of MCF10A comprised an induction of genes coding for stress responsive proteins, representing a prosurvival effect. While NAF downregulated genes encoding proteins associated to glycolipid and fatty acid biosynthesis in MDA-MB231, potentially affecting membrane biogenesis, in MCF10A, genes critical for growth control and adhesion were altered. NAFs responded to coculture with MDA-MB231 by a decrease in the expression of genes induced by TGFbeta1 and associated to motility. However, there was little change in NAFs gene expression profile influenced by MCF10A. CAFs responded to the presence of both epithelial cells inducing genes implicated in cell proliferation. Our data indicate that interactions between breast fibroblasts and basal epithelial cells resulted in alterations in the genomic profiles of both cell types which may help to clarify some aspects of this heterotypic signaling.