RESUMO
The Notch signaling has an important role in multiple cellular processes and is related to carcinogenic process. To understand the potential molecular features of the crucial Notch pathway, a comprehensive multi-omics analysis is performed to explore its contributions in cancer, mainly including analysis of somatic mutation landscape, pan-cancer expression, ncRNA regulation and potential prognostic power. The screened 22 Notch core genes are relative stable in DNA variation. Dynamic expression patterns are associated with the Notch activity, which are mainly regulated by multiple ncRNAs via interactions of ncRNA:mRNA and ceRNA networks. The Notch pathway shows a potential prognostic ability through integrating multi-omics features as well as their targets, and it is correlated with immune infiltration and maybe available drug targets, implying the potential role in individualized treatment. Collectively, all of these findings contribute to exploring crucial role of the key pathway in cancer pathophysiology and gaining mechanistic insights into cross-talks among RNAs and biological pathways, which indicates the possible application of the well-conserved Notch signaling pathway in precision medicine.
RESUMO
Synthetic lethality has been widely concerned because of its potential role in cancer treatment, which can be harnessed to selectively kill cancer cells via identifying inactive genes in a specific cancer type and further targeting the corresponding synthetic lethal partners. Herein, to obtain cancer-specific synthetic lethal interactions, we aimed to predict genetic interactions via a pan-cancer analysis from multiple molecular levels using random forest and then develop a user-friendly database. First, based on collected public gene pairs with synthetic lethal interactions, candidate gene pairs were analyzed via integrating multi-omics data, mainly including DNA mutation, copy number variation, methylation and mRNA expression data. Then, integrated features were used to predict cancer-specific synthetic lethal interactions using random forest. Finally, SLOAD (http://www.tmliang.cn/SLOAD) was constructed via integrating these findings, which was a user-friendly database for data searching, browsing, downloading and analyzing. These results can provide candidate cancer-specific synthetic lethal interactions, which will contribute to drug designing in cancer treatment that can promote therapy strategies based on the principle of synthetic lethality. Database URL http://www.tmliang.cn/SLOAD/.
Assuntos
Variações do Número de Cópias de DNA , Neoplasias , Bases de Dados Factuais , Epistasia Genética , Humanos , MutaçãoRESUMO
As one of common malignancies, prostate adenocarcinoma (PRAD) has been a growing health problem and a leading cause of cancer-related death. To obtain expression and functional relevant RNAs, we firstly screened candidate hub mRNAs and characterized their associations with cancer. Eight deregulated genes were identified and used to build a risk model (AUC was 0.972 at 10 years) that may be a specific biomarker for cancer prognosis. Then, relevant miRNAs and lncRNAs were screened, and the constructed primarily interaction networks showed the potential cross-talks among diverse RNAs. IsomiR landscapes were surveyed to understand the detailed isomiRs in relevant homologous miRNA loci, which largely enriched RNA interaction network due to diversities of sequence and expression. We finally characterized TK1, miR-222-3p and SNHG3 as crucial RNAs, and the abnormal expression patterns of them were correlated with poor survival outcomes. TK1 was found synthetic lethal interactions with other genes, implicating potential therapeutic target in precision medicine. LncRNA SNHG3 can sponge miR-222-3p to perturb RNA regulatory network and TK1 expression. These results demonstrate that TK1:miR-222-3p:SNHG3 axis may be a potential prognostic biomarker, which will contribute to further understanding cancer pathophysiology and providing potential therapeutic targets in precision medicine.
RESUMO
Prostate adenocarcinoma (PRAD), also named prostate cancer, the most common visceral malignancy, is diagnosed in male individuals. Herein, in order to obtain immune-based subtypes, we performed an integrative analysis to characterize molecular subtypes based on immune-related genes, and further discuss the potential features and differences between identified subtypes. Simultaneously, we also construct an immune-based risk model to assess cancer prognosis. Our findings showed that the two subtypes, C1 and C2, could be characterized, and the two subtypes showed different characteristics that could clearly describe the heterogeneity of immune microenvironments. The C2 subtype presented a better survival rate than that in the C1 subtype. Further, we constructed an immune-based prognostic model based on four screened abnormally expressed genes, and they were selected as predictors of the robust prognostic model (AUC = 0.968). Our studies provide reference for characterization of molecular subtypes and immunotherapeutic agents against prostate cancer, and the developed robust and useful immune-based prognostic model can contribute to cancer prognosis and provide reference for the individualized treatment plan and health resource utilization. These findings further promote the development and application of precision medicine in prostate cancer.
