Abstract
Carcinogenesis is linked with massive changes in regulation of gene networks. We used high throughput mutation and gene expression data to interrogate involvement of 278 signaling, 72 metabolic, 48 DNA repair and 47 cytoskeleton molecular pathways in cancer. Totally, we analyzed 4910 primary tumor samples with individual cancer RNA sequencing and whole exome sequencing profiles including ~1.3 million DNA mutations and representing thirteen cancer types. Gene expression in cancers was compared with the corresponding 655 normal tissue profiles. For the first time, we calculated mutation enrichment values and activation levels for these pathways. We found that pathway activation profiles were largely congruent among the different cancer types. However, we observed no correlation between mutation enrichment and expression changes both at the gene and at the pathway levels. Overall, positive median cancer-specific activation levels were seen in the DNA repair, versus similar slightly negative values in the other types of pathways. The DNA repair pathways also demonstrated the highest values of mutation enrichment. However, the signaling and cytoskeleton pathways had the biggest proportions of representatives among the outstandingly frequently mutated genes thus suggesting their initiator roles in carcinogenesis and the auxiliary/supporting roles for the other groups of molecular pathways.
Highlights
Cancer has complex pathogenesis [1] and molecular mechanisms underlying its development and progression still remain underexplored [2]
We found that metabolic pathways had the lowest that only the pathways related to nucleotide metabolism were significantly systemically up-regulated mutational burden, and revealed that only the pathways related to nucleotide metabolism were that argues some previous reports about hyperactivation of common metabolic background [65,66,67,68]
The whole dataset included information for 19 434 tumor samples of different localizations obtained from different sources but here we considered only the samples obtained from The Cancer Genome Atlas (TCGA) project because of their uniform experimental and analytic pipeline [42]
Summary
Cancer has complex pathogenesis [1] and molecular mechanisms underlying its development and progression still remain underexplored [2]. Cancer cells accumulate mutations several times faster than the normal cells [4]. It contributes to deregulation of molecular pathways including those responsible for apoptosis, cell growth, metabolism, motility and immunosuppression [5,6]. This leads to epigenetic changes that promote further malignization, e.g., through the repression of tumor suppressor genes [7].
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