Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures

Jacob Pfeil, Lauren M. Sanders, Ioannis Anastopoulos, A. Geoffrey Lyle, Alana S. Weinstein, Yuanqing Xue, Andrew Blair, Holly C. Beale, Alex Lee, Stanley G. Leung, Phuong T. Dinh, Avanthi Tayi Shah, Marcus R. Breese, W. Patrick Devine, Isabel Bjork, Sofie R. Salama, E. Alejandro Sweet-Cordero, David Haussler, Olena Morozova Vaske

Research output: Contribution to journalArticlepeer-review

Abstract

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.

Original languageEnglish (US)
Article numbere1007753
JournalPLoS Computational Biology
Volume16
Issue number4
DOIs
StatePublished - Apr 2020
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Ecology
  • Modeling and Simulation
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

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