Dataset Information

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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Publications

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]

PMID: 27397505

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Project description:Background: Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and genome-wide association studies, contributing to a "genomic gap" that limits their access to personalised medicine. While Indigenous Australians face a high burden of chronic disease and associated medication exposure, corresponding genomic and drug safety datasets are sorely lacking. Methods: To address this, we conducted a pharmacogenomic study of almost 500 individuals from a founder Indigenous Tiwi population. Whole genome sequencing was performed using short-read Illumina Novaseq6000 technology. We characterised the pharmacogenomics (PGx) landscape of this population by analysing sequencing results and associated pharmacological treatment data. Results: We observed that every individual in the cohort carry at least one actionable genotype and 77% of them carry at least three clinically actionable genotypes across 19 pharmacogenes. Overall, 41% of the Tiwi cohort were predicted to exhibit impaired CYP2D6 metabolism, with this frequency being much higher than that for other global populations. Over half of the population predicted an impaired CYP2C9, CYP2C19, and CYP2B6 metabolism with implications for the processing of commonly used analgesics, statins, anticoagulants, antiretrovirals, antidepressants, and antipsychotics. Moreover, we identified 31 potentially actionable novel variants within Very Important Pharmacogenes (VIPs), five of which were common among the Tiwi. We further detected important clinical implications for the drugs involved with cancer pharmacogenomics such as thiopurines and tamoxifen, immunosuppressants like tacrolimus and certain antivirals used in the hepatitis C treatment due to potential differences in their metabolic processing. Conclusion: The pharmacogenomic profiles generated in our study demonstrate the utility of pre-emptive PGx testing and have the potential to help guide the development and application of precision therapeutic strategies tailored to Tiwi Indigenous patients. Our research provides valuable insights on pre-emptive PGx testing and the feasibility of its use in ancestrally diverse populations, emphasizing the need for increased diversity and inclusivity in PGx investigations.

Dataset Information

A Landscape of Pharmacogenomic Interactions in Cancer.

Publications

A Landscape of Pharmacogenomic Interactions in Cancer.

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