Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach

Milcah C. Scott, Aaron L. Sarver, Katherine J. Gavin, Venugopal Thayanithy, David M. Getzy, Robert A. Newman, Gary R. Cutter, Kerstin Lindblad-Toh, William C. Kisseberth, Lawrence E. Hunter, Subbaya Subramanian, Matthew Breen, Jaime F. Modiano

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

The heterogeneous and chaotic nature of osteosarcoma has confounded accurate molecular classification, prognosis, and prediction for this tumor. The occurrence of spontaneous osteosarcoma is largely confined to humans and dogs. While the clinical features are remarkably similar in both species, the organization of dogs into defined breeds provides a more homogeneous genetic background that may increase the likelihood to uncover molecular subtypes for this complex disease. We thus hypothesized that molecular profiles derived from canine osteosarcoma would aid in molecular subclassification of this disease when applied to humans. To test the hypothesis, we performed genome wide gene expression profiling in a cohort of dogs with osteosarcoma, primarily from high-risk breeds. To further reduce inter-sample heterogeneity, we assessed tumor-intrinsic properties through use of an extensive panel of osteosarcoma-derived cell lines. We observed strong differential gene expression that segregated samples into two groups with differential survival probabilities. Groupings were characterized by the inversely correlated expression of genes associated with 'G2/M transition and DNA damage checkpoint' and 'microenvironment-interaction' categories. This signature was preserved in data from whole tumor samples of three independent dog osteosarcoma cohorts, with stratification into the two expected groups. Significantly, this restricted signature partially overlapped a previously defined, predictive signature for soft tissue sarcomas, and it unmasked orthologous molecular subtypes and their corresponding natural histories in five independent data sets from human patients with osteosarcoma. Our results indicate that the narrower genetic diversity of dogs can be utilized to group complex human osteosarcoma into biologically and clinically relevant molecular subtypes. This in turn may enhance prognosis and prediction, and identify relevant therapeutic targets.

Original languageEnglish (US)
Pages (from-to)356-367
Number of pages12
JournalBone
Volume49
Issue number3
DOIs
StatePublished - Sep 2011

Bibliographical note

Funding Information:
This work was supported in part by grants 2254 (JFM and MB) and 947 (MB, JFM, and LEH) from the AKC Canine Health Foundation; P30 CA077598 (MCC Core) and P30 CA046934 (UCCC Core) from the NIH/NCI; Faculty Research and Development (SS and JFM) from the University of Minnesota Academic Health Center; philanthropic funds from the Kate Koogler Canine Cancer Fund; and through the University of Minnesota Animal Cancer Care and Research Program/Comparative Oncology Fund. KLT is the recipient of a EURYI award from the ESF.

Keywords

  • Canine
  • Cell cycle
  • DNA damage checkpoint
  • Gene expression profiling
  • Osteosarcoma
  • Tumor microenvironment

Fingerprint Dive into the research topics of 'Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach'. Together they form a unique fingerprint.

Cite this