Fig. 7: Modeling the regulation of L1 RT by p53 using a mediation model with L1 RNA expression.
N = 3793 tumor samples with WGS, RNA, and TP53 data, excluding tumors with germline TP53 mutations. a Schematic representing the mediation model taking TP53 mutation as the independent variable, adjusted log2 of L1 RNA expression as the mediating variable, and adjusted log2 of somatic L1 RT burden as the dependent variable. The overall regression of L1 RT versus p53 reflects the sum of the mediated (blue arrow) and unmediated (red arrow) pathways. b Breakdown of total influence of p53 on L1 RT by the mediated and unmediated pathways. Total correlation between L1 RT and p53 (gray bar). Contribution of the mediated pathway to the correlation between L1 RT and p53 (blue bar). Contribution of the unmediated pathway to the correlation between L1 RT and p53 (red bar). Top axis, the standardized correlation coefficient between L1 RT and p53. Bottom axis, influence of each pathway expressed as a percent of the total correlation. Error bars indicate 95% confidence intervals determined by bootstrap resampling. Annotations to the right of the blue and red bars show the estimated percent contributions of each pathway, with 95% confidence intervals in square brackets. c Histogram of adjusted log2 L1 RNA expression in p53 mutant and wildtype tumors. Dashed lines divide the dataset into quintiles based on L1 RNA expression. d Box plots comparing log2 adjusted L1 RT burden in p53 mutant versus WT tumors, stratified by L1 RNA quintiles from (c). Center line indicates median. Box indicates interquartile range. Points more than 1.5× IQR away from the box are shown as individual outliers. Bonferroni adjusted significance level of two-sided Mann–Whitney U test comparing p53 mutant tumors to p53 WT tumors within a quintile: *p < 0.01, **p < 0.001, ***p < 0.0001. Exact p-values and effect sizes for each quintile are as follows. Q1: 1.0, 0.02; Q2: 0.43, 0.08; Q3: 5.86 × 10−5, 0.20; Q4: 2.6 × 10−7, 0.23; Q5: 1.62 × 10−27, 0.49. Ns as shown in figure. c-d) Blue bars/boxes indicate p53 mutant tumors. Orange bars/boxes indicate p53 WT tumors.
