RESUMO
We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/ß-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.
Assuntos
Carcinoma/genética , Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica , Proteoma/genética , Transcriptoma , Acetilação , Animais , Antígenos de Neoplasias/genética , Carcinoma/imunologia , Carcinoma/patologia , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/patologia , Transição Epitelial-Mesenquimal/genética , Retroalimentação Fisiológica , Feminino , Instabilidade Genômica , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Repetições de Microssatélites , Fosforilação , Processamento de Proteína Pós-Traducional , Proteoma/metabolismo , Transdução de SinaisRESUMO
Rheumatic fever (RF), caused by untreated group A streptococcal (GAS) pharyngitis, is a major cause of morbidity and mortality throughout much of the less developed world and disadvantaged populations (Indigenous and other) in the developed world. Through systematic literature searches, our group has identified potential risk factors for RF and possible interventions for its prevention. The causes can be divided into biological factors, socio-economic, and lifestyle factors and health-care systems and services. Currently, the most promising medical areas look to be improving access to health care and introducing community and school-based sore throat interventions (which aim to diagnose and treat GAS pharyngitis). We could find no convincing support for skin sepsis causing RF. Overall evidence suggests that measures that aim to alleviate poverty and crowding may also reduce the incidence of RF. In comparatively rich countries such as New Zealand and Australia, urgent measures based on available evidence should be undertaken to reduce the very striking health disparity seen with RF and its sequela, rheumatic heart disease in our at-risk populations.
