Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States

Jong Wook Kim, Omar O. Abudayyeh, Huwate Yeerna, Chen Hsiang Yeang, Michelle Stewart, Russell W. Jenkins, Shunsuke Kitajima, David J. Konieczkowski, Kate Medetgul-Ernar, Taylor Cavazos, Clarence Mah, Stephanie Ting, Eliezer M. Van Allen, Ofir Cohen, John Mcdermott, Emily Damato, Andrew J. Aguirre, Jonathan Liang, Arthur Liberzon, Gabriella AlexeJohn Doench, Mahmoud Ghandi, Francisca Vazquez, Barbara A. Weir, Aviad Tsherniak, Aravind Subramanian, Karina Meneses-Cime, Jason Park, Paul Clemons, Levi A. Garraway, David Thomas, Jesse S. Boehm, David A. Barbie, William C. Hahn, Jill P. Mesirov, Pablo Tamayo

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

The systematic sequencing of the cancer genome has led to the identification of numerous genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. We applied the methodology to the RAS pathway and identified nine distinct components that reflect transcriptional activities downstream of RAS and defined several functional states associated with patterns of transcriptional component activation that associates with genomic hallmarks and response to genetic and pharmacological perturbations. These results show that the Onco-GPS is an effective approach to explore the complex landscape of oncogenic cellular states across cancers, and an analytic framework to summarize knowledge, establish relationships, and generate more effective disease models for research or as part of individualized precision medicine paradigms.

Original languageEnglish
Pages (from-to)105-118.e9
JournalCell Systems
Volume5
Issue number2
DOIs
StatePublished - 23 Aug 2017
Externally publishedYes

Keywords

  • Bayesian nomogram
  • cellular states
  • drug sensitivity
  • genetic dependency
  • inferential model
  • matrix factorization
  • oncogenic pathway
  • oncoGPS
  • precision medicine
  • transcriptional signatures

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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