Fig. 2: Tumor suppressor genes have strikingly similar effects on the initiation and growth of KRAS G12C- and G12D-driven lung tumors.

A, B Relative size (neoplastic cells) of the tumor at the indicated percentiles of the tumor size distributions for barcoded Lenti-sgRNA/Cre vectors targeting each gene, relative to the size of the sgInert tumor at the same percentile, in G12C;Cas9 mice (n = 29 biologically independent animals) (A) and G12D;Cas9 mice (n = 48 biologically independent animals) (B) at 15 weeks post-tumor initiation. The point represents the value calculated from the initial data, and 95% confidence intervals from bootstrapping are shown. C 95th percentile relative tumor sizes (relative to sgInert) for 5 of the G12D;Cas9 study groups (see Supplementary Fig. 5A, B for comparisons between additional study groups). Each point represents the tumors initiated with one Lenti-sgRNA/Cre vector and the bars are the 95th percent confidence intervals determined by bootstrapping. Gray line indicates equal effect. Pearson r is indicated. D, E Relative size of the tumor at the 95th percentile of the tumor size distributions in G12D;Cas9 mice at 15 weeks (D) or G12D;Cas9 mice at 9 weeks (n = 25 biologically independent animals) (E) versus in G12C;Cas9 mice at 15 weeks post-tumor initiation. Each dot represents the tumors initiated from one Lenti-sgRNA/Cre vector and the bars are the 95th percent confidence intervals. Genes where the 95% CI excluded no effect in G12C;Cas9 and G12D;Cas9 mice are shown in color and some key genes are labeled. The black dotted line indicates equal effect. Spearman rank-order correlation (ρ) and Pearson correlation (r) are indicated. F–I Relative size of the tumor at the indicated percentiles (see legend in (A, B)) of the tumor size distributions for barcoded Lenti-sgRNA/Cre vectors targeting Nf1 (F), Kras^WT (G), Kmt2d (H), and Cmtr2 (I) across multiple arms of our main experiment and repeat studies in G12C;Cas9 and G12D;Cas9 mice. The significance of oncogene differences at the 95th percentile were calculated by combining the study groups for each oncogene using inverse variance weighting and comparing the resulting means and variances under a normally distributed null. Bonferroni-corrected, one-sided P values are shown for significant genes. For each study group from left to right along the x axes, data include n = 10, n = 10, n = 18, n = 13, n = 35, n = 23, and n = 33 biologically independent animals. Note that the two study groups from repeat studies in G12D;Cas9 correspond to Group 8 and Group 3 in Supplementary Fig. 5.