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

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

Affiliations

¹Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA

²Childhood Cancer Genomics Group, Department of Pediatric, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA

³Department of Microbiology and Immunology, Center for Immunology, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA

⁴Roche Sequencing Solution, Pleasanton, CA, USA

⁵University of Minnesota Genomics Center, Minneapolis, MN 55455, USA

⁶Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA

⁷Animal Cancer Care and Research Program, University of Minnesota, St. Paul 55108, USA

⁸Institute of Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA

⁹Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA

¹⁰Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA

¹¹Stem Cell Institute, University of Minnesota, UDS Institute for Engineering in Medicine, Minneapolis, MN 55455, USA

Abstract and keywords

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.

Keywords: Osteosarcoma; DNA methylation; EPIGENETIC; Comparative oncology

Links

DOI: 10.1016/j.bone.2020.115716

PubMed: 33127576

WoS: 000784088900011

History

Received: 2020-06-11

Revised: 2020-10-24

Accepted: 2020-10-26

Online: 2020-10-27