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Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data.


ABSTRACT: Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology by identifying mutation-specific targets and biomarkers.

SUBMITTER: Sinha S 

PROVIDER: S-EPMC5460027 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data.

Sinha Subarna S   Thomas Daniel D   Chan Steven S   Gao Yang Y   Brunen Diede D   Torabi Damoun D   Reinisch Andreas A   Hernandez David D   Chan Andy A   Rankin Erinn B EB   Bernards Rene R   Majeti Ravindra R   Dill David L DL  

Nature communications 20170531


Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891  ...[more]

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