Characterizing genomic alterations in cancer by complementary functional associations

Kim JW, Botvinnik OB, Abudayyeh O, Birger C, Rosenbluh J, Shrestha Y, Abazeed ME, Hammerman PS, DiCara D, Konieczkowski DJ, Johannessen CM, Liberzon A, Alizad-Rahvar AR, Alexe G, Aguirre A, Ghandi M, Greulich H, Vazquez F, Weir BA, Van Allen EM, Tsherniak A, Shao DD, Zack TI, Noble M, Getz G, Beroukhim R, Garraway LA, Ardakani M, Romualdi C, Sales G, Barbie DA, Boehm JS, Hahn WC, Mesirov JP, Tamayo P

Nature Biotechnology

May 01, 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. (Publication Abstract)

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Last updated: October 30, 2018