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 Alexe; John 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

doi:10.1016/j.cels.2017.08.002

Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States

Cell Syst. 2017 Aug 23;5(2):105-118.e9. doi: 10.1016/j.cels.2017.08.002.

Authors

Jong Wook Kim¹, Omar O Abudayyeh², Huwate Yeerna³, Chen-Hsiang Yeang⁴, Michelle Stewart², Russell W Jenkins⁵, Shunsuke Kitajima⁵, David J Konieczkowski⁶, Kate Medetgul-Ernar³, Taylor Cavazos³, Clarence Mah⁷, Stephanie Ting³, Eliezer M Van Allen⁸, Ofir Cohen⁸, John Mcdermott², Emily Damato², Andrew J Aguirre¹, Jonathan Liang², Arthur Liberzon², Gabriella Alexe⁹, John Doench², Mahmoud Ghandi², Francisca Vazquez⁸, Barbara A Weir², Aviad Tsherniak², Aravind Subramanian², Karina Meneses-Cime³, Jason Park³, Paul Clemons¹⁰, Levi A Garraway¹, David Thomas², Jesse S Boehm², David A Barbie⁸, William C Hahn¹¹, Jill P Mesirov¹², Pablo Tamayo¹³

Affiliations

¹ Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
² Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Moores Cancer Center, University of California San Diego, La Jolla, CA 92103, USA.
⁴ Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Harvard Radiation Oncology Program, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92103, USA.
⁸ Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Graduate Program in Bioinformatics, Boston University, Boston, MA 02215, USA.
¹⁰ Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
¹¹ Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹² Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92103, USA.
¹³ Cancer Program, Eli and Edythe Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92103, USA. Electronic address: [email protected].

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.

Keywords: Bayesian nomogram; cellular states; drug sensitivity; genetic dependency; inferential model; matrix factorization; oncoGPS; oncogenic pathway; precision medicine; transcriptional signatures.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Biomarkers, Tumor / metabolism
Cell Line, Tumor
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic*
Genes, ras / genetics
Genome
Humans
MAP Kinase Signaling System
Neoplasms / genetics*
Neoplasms / pathology
Precision Medicine

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding