Pan-cancer RNA-seq data stratifies tumours by some hallmarks of cancer

Numerous genetic and epigenetic alterations cause functional changes in cell biology underlying cancer. These hallmark functional changes constitute potentially tissue-independent anticancer therapeutic targets. Sanford Imagenetics researchers hypothesized that RNA-Seq identifies gene expression changes that underly those hallmarks, and thereby defines relevant therapeutic targets. To test this hypothesis, they 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. The researchers 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.

A flowchart depicting the analyses used in this study

Transcriptome profiles were first restricted to protein‐coding genes (A), then two different primary site‐correction approaches were taken to analyse the three data sets in parallel (B). Each data set was analysed using WGCNA to identify groups of genes (modules) that were co‐correlated, and variable across cancers (C). Genes found in modules were put through pathway enrichment analysis (WebGestalt) and used for hierarchical clustering (D)