Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma

Lauren J. Mills, Milcah C. Scott, Pankti Shah, Anne R. Cunanan, Archana Deshpande, Benjamin Auch, Bridget Curtin, Kenneth B. Beckman, Logan G. Spector, Aaron L. Sarver, Subbaya Subramanian, Todd A. Richmond, Jaime F. Modiano

Research output: Contribution to journalArticlepeer-review

Abstract

Osteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor protein p53 (TP53) is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples. Significance: Genome wide comparison of DNA methylation patterns in osteosarcoma across two species lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of varied mutational landscapes.

Original languageEnglish (US)
Article number115716
JournalBone
Early online dateOct 27 2020
DOIs
StateE-pub ahead of print - Oct 27 2020

Bibliographical note

Funding Information:
Work performed at University of Minnesota was supported in part by: Zach Sobiech Fund for Osteosarcoma Research of the Children's Cancer Research Fund; National Cancer Institute/NIH grants R21 CA208529, R50 CA211249, and P30 CA077598; Department of Defense (Congressionally Designated Medical Research Program) grant CA170218; Morris Animal Foundation grant D13CA-032; Karen Wyckoff Rein in Sarcoma Foundation of America; Comparative Medicine Signature Program, College of Veterinary Medicine, University of Minnesota; Animal Cancer Care and Research Program, University of Minnesota.

Funding Information:
Data analysis pipeline development was supported by Roche Sequencing Solutions, Madison. MB, PS, and TR are past or present employees of Roche Sequencing Solutions, Madison.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • Comparative oncology
  • DNA methylation
  • EPIGENETIC
  • Osteosarcoma

PubMed: MeSH publication types

  • Journal Article

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