Cancer evolution is a stochastic process both at the genome and gene levels. Most of tumors contain multiple genetic subclones, evolving in either succession or in parallel, either in a linear or branching manner, with heterogeneous genome and gene alterations, extensively rewired signaling networks, and addicted to multiple oncogenes easily switching with each other during cancer progression and medical intervention. Hundreds of discovered cancer genes are classified according to whether they function in a dominant (oncogenes) or recessive (tumor suppressor genes) manner in a cancer cell. However, there are many cancer "gene-chameleons", which behave distinctly in opposite way in the different experimental settings showing antagonistic duality. In contrast to the widely accepted view that mutant NADP(+)-dependent isocitrate dehydrogenases 1/2 (IDH1/2) and associated metabolite 2-hydroxyglutarate (R)-enantiomer are intrinsically "the drivers" of tumourigenesis, mutant IDH1/2 inhibited, promoted or had no effect on cell proliferation, growth and tumorigenicity in diverse experiments. Similar behavior was evidenced for dozens of cancer genes. Gene function is dependent on genetic network, which is defined by the genome context. The overall changes in karyotype can result in alterations of the role and function of the same genes and pathways. The diverse cell lines and tumor samples have been used in experiments for proving gene tumor promoting/suppressive activity. They all display heterogeneous individual karyotypes and disturbed signaling networks. Consequently, the effect and function of gene under investigation can be opposite and versatile in cells with different genomes that may explain antagonistic duality of cancer genes and the cell type- or the cellular genetic/context-dependent response to the same protein. Antagonistic duality of cancer genes might contribute to failure of chemotherapy. Instructive examples of unexpected activity of cancer genes and "paradoxical" effects of different anticancer drugs depending on the cellular genetic context/signaling network are discussed.
Keywords: Aneuploidy; BCR-ABL; CD95/FAS; Chromosome instability; DDR1; EF1A2; EGFR; ESPL1; FGF18; Genetic heterogeneity; HYAL1/2; IDH1/2; KIT; L1M domain containing gene 1; L1MD1; LCK; LTF; MAPK; MTOR; NAD(P)H dehydrogenase, quinone 2; NQO2; PDGFRβ; PIK3CA; PTEN; RNASET2; STAT1; TGFB3; Targeted therapy; VHL; WNT1; breakpoint cluster region-Abelson tyrosine-protein kinase; cluster of differentiation 95/cell surface death receptor; discoidin domain receptor tyrosine kinase 1; epidermal growth factor receptor tyrosine kinase; eukaryotic translation elongation factor 1 alpha; extra spindle pole bodies homolog 1; fibroblast growth factor 18; hyaluronoglucosaminidase 1/2; isocitrate dehydrogenases 1/2; lactotransferrin; lymphocyte-specific protein tyrosine kinase; mechanistic target of rapamycin serine/threonine kinase; mitogen-activated protein kinase; phosphatase and tensin homolog; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; pletelet derived growth factor receptor beta; ribonuclease T2; signal transducer and activator of transcription 1; transforming growth factor, beta 3; v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, tyrosine kinase receptor; von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; wingless-type MMTV integration site family, member 1.
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