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

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.

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“…TMB was derived from a study published by Gentles et al [17], and MSI was obtained from a study published by Bonneville et al [18]. As in previous studies [19][20][21], statistical analyses were performed using the rank-sum test, and p values less than 0.05 were considered statistically significant; R software was used for plotting.…”

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“…It is clear that other studies have also used similar associations, but without an explicit description of the mapping between hallmarks and functional annotation terms, they cannot reliably be reproduced for the comparison [ 22 – 26 ].…”