1. Characterizing genomic alterations in cancer by complementary functional associations
- Author
-
Kim, Jong Wook, Botvinnik, Olga B, Abudayyeh, Omar, Birger, Chet, Rosenbluh, Joseph, Shrestha, Yashaswi, Abazeed, Mohamed E, Hammerman, Peter S, DiCara, Daniel, Konieczkowski, David J, Johannessen, Cory M, Liberzon, Arthur, Alizad-Rahvar, Amir Reza, Alexe, Gabriela, Aguirre, Andrew, Ghandi, Mahmoud, Greulich, Heidi, Vazquez, Francisca, Weir, Barbara A, Van Allen, Eliezer M, Tsherniak, Aviad, Shao, Diane D, Zack, Travis I, Noble, Michael, Getz, Gad, Beroukhim, Rameen, Garraway, Levi A, Ardakani, Masoud, Romualdi, Chiara, Sales, Gabriele, Barbie, David A, Boehm, Jesse S, Hahn, William C, Mesirov, Jill P, and Tamayo, Pablo
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Cancer ,Human Genome ,Biotechnology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Biomarkers ,Tumor ,Chromosome Mapping ,Drug Resistance ,Neoplasm ,Genes ,Neoplasm ,Genetic Predisposition to Disease ,Genome ,Human ,Genome-Wide Association Study ,Humans ,Mutation ,Neoplasm Proteins ,Neoplasms ,Polymorphism ,Single Nucleotide ,Signal Transduction - Abstract
Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.
- Published
- 2016