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Pan-cancer RNA-seq data stratifies tumours by some hallmarks of cancer
F Graeme Frost1, Praveen F Cherukuri1,2,3, Samuel Milanovich2,3,4
1Sanford Imagenetics, Sioux Falls, SD, USA.
Abstract:
Numerous genetic and epigenetic alterations cause functional changes in cell biology underlying cancer. These hallmark functional changes constitute potentially tissue-independent anticancer therapeutic targets. We hypothesized that RNA-Seq identifies gene expression changes that underly those hallmarks, and thereby defines relevant therapeutic targets. To test this hypothesis, we analysed the publicly available TCGA-TARGET-GTEx gene expression data set from the University of California Santa CruzToil recompute project using WGCNA to delineate co-correlated 'modules' from tumour gene expression profiles and functional enrichment of these modules to hierarchically cluster tumours. This stratified tumours according to T cell activation, NK-cell activation, complement cascade, ATM, Rb, angiogenic, MAPK, ECM receptor and histone modification signalling. These correspond to the cancer hallmarks of avoiding immune destruction, tumour-promoting inflammation, evading growth suppressors, inducing angiogenesis, sustained proliferative signalling, activating invasion and metastasis, and genome instability and mutation. This approach did not detect pathways corresponding to the cancer enabling replicative immortality, resisting cell death or deregulating cellular energetics hallmarks. We conclude that RNA-Seq stratifies tumours along some, but not all, hallmarks of cancer and, therefore, could be used in conjunction with other analyses collectively to inform precision therapy.
Insights
RNA sequencing (RNA-Seq) can identify gene expression changes linked to cancer hallmarks, aiding in the discovery of new therapeutic targets. This method effectively stratifies tumors based on several key cancer hallmarks, but not all.
Area of Science:
- Genomics and Molecular Biology
- Cancer Research
- Bioinformatics
Background:
- Genetic and epigenetic alterations drive cancer development through functional changes in cell biology.
- These cancer hallmarks represent potential tissue-independent therapeutic targets.
- RNA sequencing (RNA-Seq) is a powerful tool for analyzing gene expression patterns.
Purpose of the Study:
- To test the hypothesis that RNA-Seq can identify gene expression changes underlying cancer hallmarks.
- To determine if these identified changes can define relevant therapeutic targets.
- To stratify tumors based on cancer hallmarks using gene expression data.
Main Methods:
- Analysis of the TCGA-TARGET-GTEx gene expression dataset.
- Application of Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene modules.
- Functional enrichment analysis of modules for hierarchical tumor clustering.
Main Results:
- RNA-Seq analysis stratified tumors according to hallmarks such as immune destruction avoidance, inflammation, growth suppressor evasion, angiogenesis, proliferative signaling, invasion/metastasis, and genome instability.
- Specific signaling pathways identified included T cell activation, NK-cell activation, complement cascade, ATM, Rb, angiogenic, MAPK, ECM receptor, and histone modification.
- Pathways related to replicative immortality, resisting cell death, and deregulating cellular energetics were not detected by this approach.
Conclusions:
- RNA-Seq effectively stratifies tumors based on a subset of the cancer hallmarks.
- This approach can inform precision therapy by identifying relevant molecular targets.
- Integration with other analytical methods may provide a more comprehensive understanding of cancer hallmarks.
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