A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival

Rodrigo Guarischi-Sousa; Jhonatas S Monteiro; Lilian C Alecrim; Jussara S Michaloski; Laura B Cardeal; Elisa N Ferreira; Dirce M Carraro; Diana N Nunes; Emmanuel Dias-Neto; Jüri Reimand; Paul C Boutros; João C Setubal; Ricardo J Giordano

doi:10.1371/journal.pgen.1008482

A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival

PLoS Genet. 2019 Dec 17;15(12):e1008482. doi: 10.1371/journal.pgen.1008482. eCollection 2019 Dec.

Authors

Affiliations

¹ Biochemistry Department, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
² Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
³ International Research Center (CIPE) A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
⁴ Laboratory of Neurosciences (LIM27), Institute & Department of Psychiatry, University of São Paulo, São Paulo, Brazil.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Human Genetics, University of California Los Angeles (UCLA), Los Angeles, CA, United States of America.

Abstract

The specific genes and molecules that drive physiological angiogenesis differ from those involved in pathological angiogenesis, suggesting distinct mechanisms for these seemingly related processes. Unveiling genes and pathways preferentially associated with pathologic angiogenesis is key to understanding its mechanisms, thereby facilitating development of novel approaches to managing angiogenesis-dependent diseases. To better understand these different processes, we elucidated the transcriptome of the mouse retina in the well-accepted oxygen-induced retinopathy (OIR) model of pathological angiogenesis. We identified 153 genes changed between normal and OIR retinas, which represent a molecular signature relevant to other angiogenesis-dependent processes such as cancer. These genes robustly predict the survival of breast cancer patients, which was validated in an independent 1,000-patient test cohort (40% difference in 15-year survival; p = 2.56 x 10-21). These results suggest that the OIR model reveals key genes involved in pathological angiogenesis, and these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Breast Neoplasms / genetics*
Breast Neoplasms / mortality
Disease Models, Animal
Female
Gene Expression Profiling / methods*
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
High-Throughput Nucleotide Sequencing
Humans
Mice
Middle Aged
Neovascularization, Pathologic / chemically induced
Neovascularization, Pathologic / genetics*
Neovascularization, Pathologic / mortality
Oxygen / adverse effects*
Retina / chemistry*
Retina / drug effects
Sequence Analysis, RNA

Substances

Oxygen

Grants and funding

This work was supported by research grants from: São Paulo Research Foundation (FAPESP; www.fapesp.br) (grant 2008/54.806-8 and 2016/22.645-1 to R.J.G., and fellowships 2012/15.197-1 and 2014/21.360-8 to R.G.S.), the National Council for Scientific and Technological Development (CNPq; www.cnpq.br) (grant number 560.860/2010) (to R.J.G.) and research fellowships (to J.C.S. and R.J.G). This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Brasil (CAPES; www.capes.gov.br), Finance Code 001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.