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Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced de-novo mutation in survival outliers of glioblastoma

Taeyoung Hwang, Dimitrios Mathios, Kerrie L McDonald, Irene Daris, Sung-Hye Park, Peter C Burger, Sojin Kim, Yun-Sik Dho, Hruban Carolyn, Chetan Bettegowda, Joo Heon Shin, Michael Lim, View ORCID ProfileChul-Kee Park
doi: https://doi.org/10.1101/302042
Taeyoung Hwang
1Lieber Institute for Brain Development, Baltimore, MD 21205, USA
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Dimitrios Mathios
2Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Kerrie L McDonald
3Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia
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Irene Daris
3Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia
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Sung-Hye Park
4Department of Pathology, Seoul National University College of Medicine, Seoul 03080, South Korea
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Peter C Burger
5Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Sojin Kim
6Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, South Korea
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Yun-Sik Dho
6Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, South Korea
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Hruban Carolyn
7Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Chetan Bettegowda
2Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Joo Heon Shin
1Lieber Institute for Brain Development, Baltimore, MD 21205, USA
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Michael Lim
2Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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  • For correspondence: nsckpark@snu.ac.kr mlim3@jhmi.edu
Chul-Kee Park
6Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, South Korea
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  • ORCID record for Chul-Kee Park
  • For correspondence: nsckpark@snu.ac.kr mlim3@jhmi.edu
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Abstract

The study of survival outliers of glioblastoma (GBM) can have important implications on gliomagenesis as well as in the identification of ways to alter clinical course on this almost uniformly lethal cancer type. However, current studied epigenetic and genetic signatures of the GBM outliers have failed to identify unifying criteria to characterize this unique group of patients. In this study, we profiled the global DNA methylation pattern of mainly IDH1 wild type survival outliers of glioblastoma and performed comprehensive enrichment analyses with genomic and epigenomic signatures. We found that the genome of long-term survivors in glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. The hypomethylation pattern at the region distant from CGI is associated with lower rates of de novo mutations while the hypermethylation at CGIs correlates with transcriptional downregulation of genes involved in cancer progression pathways. These results extend our understanding of DNA methylation of survival outliers in glioblastoma in a genome-wide level, and provide insight on the potential impact of DNA hypomethylation in cancer genome.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 16, 2018.
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Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced de-novo mutation in survival outliers of glioblastoma
Taeyoung Hwang, Dimitrios Mathios, Kerrie L McDonald, Irene Daris, Sung-Hye Park, Peter C Burger, Sojin Kim, Yun-Sik Dho, Hruban Carolyn, Chetan Bettegowda, Joo Heon Shin, Michael Lim, Chul-Kee Park
bioRxiv 302042; doi: https://doi.org/10.1101/302042
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Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced de-novo mutation in survival outliers of glioblastoma
Taeyoung Hwang, Dimitrios Mathios, Kerrie L McDonald, Irene Daris, Sung-Hye Park, Peter C Burger, Sojin Kim, Yun-Sik Dho, Hruban Carolyn, Chetan Bettegowda, Joo Heon Shin, Michael Lim, Chul-Kee Park
bioRxiv 302042; doi: https://doi.org/10.1101/302042

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