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

Nat Commun. 2017 May 31:8:15580. doi: 10.1038/ncomms15580.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Animals
  • Cell Line, Tumor
  • Computational Biology / methods*
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • MCF-7 Cells
  • Male
  • Mice
  • Neoplasm Transplantation
  • Precision Medicine / methods
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Synthetic Lethal Mutations / genetics*
  • Transplantation, Heterologous


  • RNA, Small Interfering