Fig. 3.

The germline component of 17-AAG drug susceptibility. a Quantile–quantile plot of negative log P values from genome-wide association tests of 17-AAG susceptibility, considering germline variants (back) and somatic mutations (green). The most associated (lead) variant rs12595927 is in tight linkage disequilibrium with the known causal variant for this associations (rs1800566, e.g., ref.¹⁸, r² = 1 in European populations). b Scatter plot between NQO1 gene expression (x-axis) and 17-AAG drug susceptibility (y-axis). Dots correspond to individual cell lines stratified by genotype at the rs1800566 locus (yellow: TT allele, blue: CC/CT allele). Box plots show the effect of the rs1800566 locus on gene expression (top panel) and drug susceptibility (right panel). Whereas NQO1 expression level is not associated with the germline variant, rs1800566 modulates the association between NQO1 expression level and drug susceptibility. The combination of high expression levels of NQO1 together with a CC or CT genotype is associated with the largest drug response. Boxes extend from the lower quartile (Q₁) of the data to the upper quartile (Q₂) of the data, whiskers show the range of the data (after excluding outliers), fliers show outliers and the red lines show the medians. Outliers are defined by the standard condition x < Q₁ −1.5(Q₂ −Q₁) ∨ x > Q₂ + 1.5(Q₂ −Q₁). c Scatter plot between NQO1 expression level (x-axis) and 17-AAG drug susceptibility (y-axis), stratified by tissue type. d Lower panel: Mean drug efficacy of AUY922 and 17-AAG as a function of NQO1 expression and stratified for rs1800566 genotype. Colours indicated the genotype group with triangles corresponding to AUY922 response and circles denoting 17-AAG response. Shaded areas indicate plus or minus one standard error of the mean drug response. Top panel: number of cell lines in stratified groups. AUY922 is more effective than 17-AAG for low NQO1 expression. In cell lines with a CT and CC (rs1800566) germline background and high expression of NQO1, the efficacy of 17-AAG is comparable or larger than AUY922. e Mode of action for 17-AAG and AUY922. f Frequency of NQO1 germline variants in different human populations. Data for rs1800566 extracted from EnsEMBL