Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer

Maria Arechederra, Fabrice Daian, Annie Yim, Sehrish K. Bazai, Sylvie Richelme, Rosanna Dono, Andrew J. Saurin, Bianca H. Habermann and Flavio Maina ()
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Maria Arechederra: Aix Marseille Univ
Fabrice Daian: Aix Marseille Univ
Annie Yim: Max Planck Institute of Biochemistry
Sehrish K. Bazai: Aix Marseille Univ
Sylvie Richelme: Aix Marseille Univ
Rosanna Dono: Aix Marseille Univ
Andrew J. Saurin: Aix Marseille Univ
Bianca H. Habermann: Aix Marseille Univ
Flavio Maina: Aix Marseille Univ

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Epigenetic modifications such as aberrant DNA methylation reshape the gene expression repertoire in cancer. Here, we used a clinically relevant hepatocellular carcinoma (HCC) mouse model (Alb-R26Met) to explore the impact of DNA methylation on transcriptional switches associated with tumorigenesis. We identified a striking enrichment in genes simultaneously hypermethylated in CpG islands (CGIs) and overexpressed. These hypermethylated CGIs are located either in the 5′-UTR or in the gene body region. Remarkably, such CGI hypermethylation accompanied by gene upregulation also occurs in 56% of HCC patients, which belong to the “HCC proliferative-progenitor” subclass. Most of the genes upregulated and with hypermethylated CGIs in the Alb-R26Met HCC model undergo the same change in a large proportion of HCC patients. Among reprogrammed genes, several are well-known oncogenes. For others not previously linked to cancer, we demonstrate here their action together as an “oncogene module”. Thus, hypermethylation of gene body CGIs is predictive of elevated oncogene levels in cancer, offering a novel stratification strategy and perspectives to normalise cancer gene dosages.

Date: 2018
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DOI: 10.1038/s41467-018-05550-5

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