A Landscape of Pharmacogenomic Interactions in Cancer

Francesco Iorio,Graham R Bignell,Nanne Aben,Mathew J Garnett,Nathanael S Gray,Thomas Cokelaer,Tinghu Zhang,Tatiana Mironenko,Manel Esteller,Maryam Soleimani,David Tamborero,Holger Heyn,Jinhua Wang,Syd Barthorpe,Xeni Mitropoulos,Heshani De Silva,Sergi Sayols,Ewald Van Dyk,Regina K Egan,Cyril H Benes,Michael P Menden,Patricia Greninger,Michael R Stratton,Ultan Mcdermott,Xianming Deng,Han Chang,Qingsong Liu,Howard Lightfoot,Daniel A Haber,Núria López‐Bigas ,Julio Sáez-Rodríguez ,Lodewyk Wessels ,Laura L Richardson ,Theo Knijnenburg ,Petra Ross‐Macdonald ,Michaël Schubert ,Emanuel Gonçalvès ,Sebastián Morán ,Daniël J Vis

doi:10.1016/j.cell.2016.06.017

Abstract

SummarySystematic 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.

Highlights

Cancers arise because of the acquisition of somatic alterations in their genomes that alter the function of key cancer genes (Stratton et al, 2009)
Studies from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have generated comprehensive catalogs of the cancer genes involved in tumorigenesis across a broad range of cancer types (Lawrence et al, 2014; Tamborero et al, 2013b; Zack et al, 2013)
Oncogenic Alterations in Human Tumors We built a comprehensive map of the oncogenic alterations in human tumors using data from TCGA, ICGC, and other studies (Figure 1A; Table S1C)

Summary

Introduction

Cancers arise because of the acquisition of somatic alterations in their genomes that alter the function of key cancer genes (Stratton et al, 2009). A number of these alterations are implicated as determinants of treatment response in the clinic (Chapman et al, 2011; Mok et al, 2009; Shaw et al, 2013). Studies from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have generated comprehensive catalogs of the cancer genes involved in tumorigenesis across a broad range of cancer types (Lawrence et al, 2014; Tamborero et al, 2013b; Zack et al, 2013). The emerging landscape of oncogenic alterations in cancer points to a hierarchy of likely functional processes and pathways that may guide the future treatment of.

Results

Discussion

Conclusion