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The germline genetic component of drug sensitivity in cancer cell lines

Patients with seemingly the same tumour can respond very differently to treatment. There are strong, well-established effects of somatic mutations on drug efficacy, but there is at-most anecdotal evidence of a germline component to drug response. Here, we report a systematic survey of how inherited...

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Bibliographische Detailangaben
Hauptverfasser: Menden, Michael (VerfasserIn) , Casale, Francesco Paolo (VerfasserIn) , Stephan, Johannes (VerfasserIn) , Bignell, Graham R. (VerfasserIn) , Iorio, Francesco (VerfasserIn) , McDermott, Ultan (VerfasserIn) , Garnett, Mathew J. (VerfasserIn) , Sáez Rodríguez, Julio (VerfasserIn) , Stegle, Oliver (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 23 August 2018
In: Nature Communications
Year: 2018, Jahrgang: 9
ISSN:2041-1723
DOI:10.1038/s41467-018-05811-3
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-018-05811-3
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Verfasserangaben:Michael P. Menden, Francesco Paolo Casale, Johannes Stephan, Graham R. Bignell, Francesco Iorio, Ultan McDermott, Mathew J. Garnett, Julio Saez-Rodriguez & Oliver Stegle
Beschreibung
Zusammenfassung:Patients with seemingly the same tumour can respond very differently to treatment. There are strong, well-established effects of somatic mutations on drug efficacy, but there is at-most anecdotal evidence of a germline component to drug response. Here, we report a systematic survey of how inherited germline variants affect drug susceptibility in cancer cell lines. We develop a joint analysis approach that leverages both germline and somatic variants, before applying it to screening data from 993 cell lines and 265 drugs. Surprisingly, we find that the germline contribution to variation in drug susceptibility can be as large or larger than effects due to somatic mutations. Several of the associations identified have a direct relationship to the drug target. Finally, using 17-AAG response as an example, we show how germline effects in combination with transcriptomic data can be leveraged for improved patient stratification and to identify new markers for drug sensitivity.
Beschreibung:Gesehen am 30.03.2020
Beschreibung:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-018-05811-3

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