Abstract
Most cancer driver genes are involved in generic cellular processes such as DNA repair, cell proliferation and cell adhesion, yet their mutations are often confined to specific cancer types. To resolve this paradox, we explained mutation frequencies of selected genes across tumor types with four features in the corresponding normal tissues from cancer-free subjects: mRNA expression and chromatin accessibility of mutated genes, mRNA expressions of their neighbors in curated pathways and the protein-protein interaction network. Encouragingly, these transcriptomic/epigenomic features in normal tissues were closely associated with mutational/functional characteristics in tumors. First, chromatin accessibility was a necessary but not sufficient condition for frequent mutations. Second, variations of mutation frequencies in selected genes across tissue types were significantly associated with all four features. Third, the genes possessing significant associations between mutation frequency variations and pathway gene expression were enriched with documented cancer genes. We further proposed a novel bivariate gene set enrichment analysis and confirmed that the pathway gene expression was the dominant factor in cancer gene enrichment. These findings shed lights on the functional roles of genes in normal tissues in shaping the mutational landscape during tumor genome evolution.
Highlights
Cancer cells harbor a large number of mutations on diverse genes with a wide range of occurrence frequencies[1]
APC and beta catenin are members of the Wnt pathway[34]; EGFR, BRAF and FLT3 are members of the Ras pathway[48,49,50]; BRCA1 and BRCA2 are involved in DNA repair[45]
We divided genes into “EpiON” and “EpiOFF” groups according to their chromatin accessibility states
Summary
Cancer cells harbor a large number of mutations on diverse genes with a wide range of occurrence frequencies[1]. APC and beta catenin are members of the Wnt pathway[34]; EGFR, BRAF and FLT3 are members of the Ras pathway[48,49,50]; BRCA1 and BRCA2 are involved in DNA repair[45] Those processes are essential for the development and maintenance of almost all tissue types. Mutations on the gene confer no selective advantage and do not appear frequently in the population This line of reasoning motivated us to investigate the roles of features in normal tissues in explaining cancer type-specific mutations of genes undergoing selection in cancer genome evolution. The encouraging results serve as an early step toward understanding molecular and clinical characteristics of cancers from an evolutionary perspective
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