RESUMO
The IntOGen-mutations platform (http://www.intogen.org/mutations/) summarizes somatic mutations, genes and pathways involved in tumorigenesis. It identifies and visualizes cancer drivers, analyzing 4,623 exomes from 13 cancer sites. It provides support to cancer researchers, aids the identification of drivers across tumor cohorts and helps rank mutations for better clinical decision-making.
Assuntos
Mutação , Neoplasias/genética , Exoma , Humanos , Neoplasias/classificação , Neoplasias/patologiaRESUMO
BACKGROUND: Chromatin regulatory factors are emerging as important genes in cancer development and are regarded as interesting candidates for novel targets for cancer treatment. However, we lack a comprehensive understanding of the role of this group of genes in different cancer types. RESULTS: We have analyzed 4,623 tumor samples from thirteen anatomical sites to determine which chromatin regulatory factors are candidate drivers in these different sites. We identify 34 chromatin regulatory factors that are likely drivers in tumors from at least one site, all with relatively low mutational frequency. We also analyze the relative importance of mutations in this group of genes for the development of tumorigenesis in each site, and indifferent tumor types from the same site. CONCLUSIONS: We find that, although tumors from all thirteen sites show mutations in likely driver chromatin regulatory factors, these are more prevalent in tumors arising from certain tissues. With the exception of hematopoietic, liver and kidney tumors, as a median, the mutated factors are less than one fifth of all mutated drivers across all sites analyzed. We also show that mutations in two of these genes, MLL and EP300, correlate with broad expression changes across cancer cell lines, thus presenting at least one mechanism through which these mutations could contribute to tumorigenesis in cells of the corresponding tissues.
Assuntos
Transformação Celular Neoplásica/genética , Cromatina/metabolismo , Proteína p300 Associada a E1A/genética , Regulação Neoplásica da Expressão Gênica , Proteína de Leucina Linfoide-Mieloide/genética , Neoplasias/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Cromatina/química , Montagem e Desmontagem da Cromatina , Proteína p300 Associada a E1A/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Histona-Lisina N-Metiltransferase , Humanos , Taxa de Mutação , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Mapeamento de Interação de ProteínasRESUMO
Global changes in the epigenome are increasingly being appreciated as key events in cancer progression. The pathogenic role of enhancer of zeste homolog 2 (EZH2) has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression; however, little is known about relationship of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. Here we show that through expression analysis of genomic regions with H3K27 trimethylation (H3K27me3) and EZH2 binding, breast cancer patients can be stratified into good and poor prognostic groups independent of known cancer gene signatures. The EZH2-bound regions were downregulated in tumors characterized by aggressive behavior, high expression of cell cycle genes, and low expression of developmental and cell adhesion genes. Depletion of EZH2 in breast cancer cells significantly increased expression of the top altered genes, decreased proliferation, and improved cell adhesion, indicating a critical role played by EZH2 in determining the cancer phenotype.
Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Complexo Repressor Polycomb 2/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste , Transição Epitelial-Mesenquimal/genética , Feminino , Células HEK293 , Histonas/metabolismo , Humanos , Immunoblotting , Estimativa de Kaplan-Meier , Células MCF-7 , Metilação , Modelos Genéticos , Complexo Repressor Polycomb 2/metabolismo , Prognóstico , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting.