Genome-wide DNA methylation patterns reveal clinically relevant predictive and prognostic subtypes in human osteosarcoma

Christopher E Lietz,G Petur Nielsen,Kevin A Raskin,Erik T Newman,Martin J Aryee,Ziying Zhang,Caroline A Luscko,David H Xiang,Santiago A Lozano-Calderon,Edwin Choy,David H Ebb,Dimitrios Spentzos,Andrew D Kelly,Benjamin Haibe-Kains,Gregory M Cote

doi:10.1038/s42003-022-03117-1

Abstract

Aberrant methylation of genomic DNA has been reported in many cancers. Specific DNA methylation patterns have been shown to provide clinically useful prognostic information and define molecular disease subtypes with different response to therapy and long-term outcome. Osteosarcoma is an aggressive malignancy for which approximately half of tumors recur following standard combined surgical resection and chemotherapy. No accepted prognostic factor save tumor necrosis in response to adjuvant therapy currently exists, and traditional genomic studies have thus far failed to identify meaningful clinical associations. We studied the genome-wide methylation state of primary tumors and tested how they predict patient outcomes. We discovered relative genomic hypomethylation to be strongly predictive of response to standard chemotherapy. Recurrence and survival were also associated with genomic methylation, but through more site-specific patterns. Furthermore, the methylation patterns were reproducible in three small independent clinical datasets. Downstream transcriptional, in vitro, and pharmacogenomic analysis provides insight into the clinical translation of the methylation patterns. Our findings suggest the assessment of genomic methylation may represent a strategy for stratifying patients for the application of alternative therapies.

Highlights

Aberrant methylation of genomic DNA has been reported in many cancers
Our group has demonstrated that microRNA expression patterns from various genomic loci, predominantly those from the 14q32 non-coding region, are predictive of clinical outcome and capture prognostic information distinct from that conveyed by pathologic necrosis and/or metastatic status[24–27]
Available information indicates most patients were treated with standard chemotherapy (methotrexate, Adriamycin, and cisplatin (MAP)), treatment information is not available for all patients

Summary

Introduction

Aberrant methylation of genomic DNA has been reported in many cancers. Specific DNA methylation patterns have been shown to provide clinically useful prognostic information and define molecular disease subtypes with different response to therapy and long-term outcome. When pathologically assessed response to chemotherapy was used as a marker to stratify patients for alternate or intensified adjuvant therapies in a large international clinical trial (EURAMOS), it did not result in a survival benefit[6,22,23] This failure underscores the need for improved prognostic biomarkers to assist in the development of therapies. Induction of global hypomethylation has been demonstrated to result in chromosomal instability and OSA formation in animal models[28], and in vitro treatment with demethylating agents has been shown to reverse epigenetically silenced tumor suppressor genes and inhibit OSA cell growth[29–31] These observations are consistent with data showing that DNA methylation inhibitors preferentially affect genes that are expressed in normal tissue and silenced in cancer[32–34]. Genome-wide methylation signatures in clinical samples have been utilized to distinguish OSA from Ewing or synovial sarcoma, underscoring the notion of epigenetically-modified molecular phenotypes[35], and global methylation patterns have been shown to be prognostic of relapse risk in a small OSA clinical cohort[36]

Methods

Results

Conclusion