Genome-wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types

Dimitrios Mathios, Taeyoung Hwang, Yuanxuan Xia, Jillian Phallen, Yuan Rui, Alfred P. See, Russell Maxwell, Zineb Belcaid, Joshua Casaos, Peter C. Burger, Kerrie L. McDonald, Gary L. Gallia, Leslie Cope, Mihoko Kai, Henry Brem, Drew M. Pardoll, Patrick Ha, Jordan J. Green, Victor E. Velculescu, Chetan BettegowdaChul Kee Park, Michael Lim

Research output: Contribution to journalArticlepeer-review

Abstract

DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.

Original languageEnglish (US)
Pages (from-to)3425-3435
Number of pages11
JournalInternational Journal of Cancer
Volume145
Issue number12
DOIs
StatePublished - Dec 15 2019

Keywords

  • TCGA
  • ZMIZ1
  • glioblastoma
  • intragenic DNA methylation
  • prognostic cancer marker

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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