Characterizing genomic alterations in cancer by complementary functional associations.
Jong Wook KimOlga B BotvinnikOmar AbudayyehChet BirgerJoseph RosenbluhYashaswi ShresthaMohamed E AbazeedPeter S HammermanDaniel DiCaraDavid J KonieczkowskiCory M JohannessenArthur LiberzonAmir Reza Alizad-RahvarGabriela AlexeAndrew AguirreMahmoud GhandiHeidi GreulichFrancisca VazquezBarbara A WeirEliezer M Van AllenAviad TsherniakDiane D ShaoTravis I ZackMichael NobleGad GetzRameen BeroukhimLevi A GarrawayMasoud ArdakaniChiara RomualdiGabriele SalesDavid A BarbieJesse S BoehmWilliam C HahnJill P MesirovPablo TamayoPublished in: Nature biotechnology (2016)
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.
Keyphrases
- copy number
- papillary thyroid
- mitochondrial dna
- genome wide
- squamous cell
- dna methylation
- endothelial cells
- transcription factor
- oxidative stress
- gene expression
- cell proliferation
- lymph node metastasis
- emergency department
- epithelial mesenchymal transition
- squamous cell carcinoma
- signaling pathway
- smoking cessation
- heat shock protein
- replacement therapy