RESUMO
Transcriptional profile-based subtypes of cancer are often viewed as identifying different diseases from the same tissue origin. Understanding the mechanisms driving the subtypes may be key in development of novel therapeutics but is challenged by lineage-specific expression signals. Using a t-test statistics approach, we compared gene expression subtypes across 12 tumor types, which identified eight transcriptional superclusters characterized by commonly activated disease pathways and similarities in gene expression. One of the largest superclusters was determined by the upregulation of a proliferation signature, significant enrichment in TP53 mutations, genomic loss of CDKN2A (p16(ARF)), evidence of increased numbers of DNA double strand breaks and high expression of cyclin B1 protein. These correlations suggested that abrogation of the P53-mediated apoptosis response to DNA damage results in activation of cell cycle pathways and represents a common theme in cancer. A second consistent pattern, observed in 9 of 11 solid tumor types, was a subtype related to an activated tumor-associated stroma. The similarity in transcriptional footprints across cancers suggested that tumor subtypes are commonly unified by a limited number of molecular themes.
Assuntos
Ciclo Celular/genética , Expressão Gênica/genética , Genes p53/genética , Mutação/genética , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Ciclina B1/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Dano ao DNA/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Perda de Heterozigosidade/genéticaRESUMO
Here we address the question of the degree to which genes within experimentally characterized operons in one organism (Escherichia coli) are conserved in other genomes. We found that two genes adjacent within an operon are more likely both to have an ortholog in other organisms, regardless of relative position, than genes adjacent on the same strand but in two different transcription units. They are also more likely to occur next to, or fused to, one another in other genomes. Genes frequently conserved adjacent to each other, especially among evolutionarily distant species, must be part of the same transcription unit in most of them.
