Fig. 4: Identification of genomic variants that are potentially associated with a cardiotoxic response.

Whole genome sequencing of our six cell lines¹⁶ was used to identify alleles in our cell lines at known variant positions. A See text and methods for details of our pipeline for identification of potential genomic variants involved in PK/PD or induced SCP activities for a drug of interest. Flow chart is used with permission from Mount Sinai Health System, licensed under CC BY. B Clustering of DEGs within the daunorubicin-selective subspace reveals an outlier response in cell line MSN09 after daunorubicin treatment. C The identified variant rs2229774 in cell line MSN09 maps to the coding region of the transcription factor RARG regulating the expression of TOP2B and ABCB8, both involved in PK/PD of daunorubicin and doxorubicin that induce an outlier response in this cell line. D Enrichment significance ranks for “WNT-Beta-catenin signaling pathway” obtained by analysis of upregulated genes after daunorubicin or doxorubicin treatment of indicated cell lines. The cell line MSN09 (purple) contains the rs2229774 mutation in the RARG gene. Field colors change from bright to dark yellow with increasing ranks. ‘>’ indicates that the SCP was not predicted or predicted with a rank > 99. E In total, we identified 213 and 201 potential variants associated with TIC or AIC by interference with PK/PD mechanisms, respectively. Variants mapping to multiple gene classes are split equally among them to prevent double counting. Drug names are colored according to their class (orange: Small molecule kinase inhibitors (KI), red: monoclonal antibodies against KIs, purple: anthracyclines). F We compared the overlap of identified SCP genes associated with a cardiotoxic or non-cardiotoxic response to genes associated with inherited DCM or HCM, either within the HuGE Phenopedia database or identified in GWAS. TWAS: transcription-wide-association studies. G Variants that meet our population-wide criteria were mapped to up- and downregulated level -2, -3 and -4 SCPs that we predicted as indicative for TIC. Variants that map to identified SCPs of multiple levels are only counted for the lowest level SCPs (higher level numbers) to prevent double counting. Drug names are colored as described in (E). H Up- and downregulated SCPs associated with a cardiotoxic response were mapped back to the cardiotoxic TKIs that induce them. Numbers in brackets show identified variants for each SCP gene. Blue indicates that the SCP is a level-3 SCP.