Selective DNA methylation in cancers controls collateral damage induced by large structural variations
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Vakul Mohanty1, Ogulsheker Akmamedova2 and Kakajan Komurov3
1Systems Biology and Physiology Graduate Program, University of Cincinnati, OH, USA
2Graduate program in Mathematics, Fatih University, Istanbul, Turkey
3Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
Kakajan Komurov, email: [email protected]
Keywords: TCGA, computational cancer biology
Received: April 11, 2016 Accepted: June 06, 2016 Published: July 08, 2016
Chromosomal instability is a hallmark of human cancers, and is characterized by large structural variations in the genome. Such large structural variations are expected to create intrinsic collateral stress due to gene dosage changes in many genes that are co-deleted or co-amplified in large chromosomal segments (onco-passenger genes). We show that the tumor-toxic effects of gene dosage changes of onco-passenger genes are compensated by the uncoupling of their copy number variations from their expression by means of selective DNA methylation. For example, collateral co-amplification of genes in tumor suppressor pathways, such as the TGF-β and inflammatory signaling pathways, are compensated by DNA hypermethylation to suppress their overexpression, while collateral deletion of pro-oncogenic genes are compensated by DNA hypomethylation to promote their expression from the single remaining allele. Our work reveals an important tumorigenic mechanism of regulation of toxic gene copy number imbalance in tumor cells arising from chromosomal instability, and suggests that targeting the DNA methylation machinery may prevent compensatory regulation of onco-passenger gene expression in chromosomally unstable cancers, and re-activate dormant tumor suppressor pathways for effective therapy.
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