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A Landscape of Pharmacogenomic Interactions in Cancer.


ABSTRACT: Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.

SUBMITTER: Iorio F 

PROVIDER: S-EPMC4967469 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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A Landscape of Pharmacogenomic Interactions in Cancer.

Iorio Francesco F   Knijnenburg Theo A TA   Vis Daniel J DJ   Bignell Graham R GR   Menden Michael P MP   Schubert Michael M   Aben Nanne N   Gonçalves Emanuel E   Barthorpe Syd S   Lightfoot Howard H   Cokelaer Thomas T   Greninger Patricia P   van Dyk Ewald E   Chang Han H   de Silva Heshani H   Heyn Holger H   Deng Xianming X   Egan Regina K RK   Liu Qingsong Q   Mironenko Tatiana T   Mitropoulos Xeni X   Richardson Laura L   Wang Jinhua J   Zhang Tinghu T   Moran Sebastian S   Sayols Sergi S   Soleimani Maryam M   Tamborero David D   Lopez-Bigas Nuria N   Ross-Macdonald Petra P   Esteller Manel M   Gray Nathanael S NS   Haber Daniel A DA   Stratton Michael R MR   Benes Cyril H CH   Wessels Lodewyk F A LFA   Saez-Rodriguez Julio J   McDermott Ultan U   Garnett Mathew J MJ  

Cell 20160707 3


Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensit  ...[more]

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