Fig. 3: TRIM28-dependent developmental heterogeneity primes cancer outcomes.
a, Body mass distribution at 16 weeks by genotype. Each dot represents one male. Box plots show 25th, 50th (median) and 75th percentiles, with whiskers extending to 1.5 × interquartile range of the hinge and outliers plotted individually. Two-sided Levene’s test, Benjamini–Hochberg adjusted. Significance for adjusted P value (Padj) < 0.05: WT versus Trim28+/D9, Padj = 0.0025152 (F = 13.482); WT versus Trp53R270H/+, Padj = 0.2031600 (F = 1.9399); WT versus Trp53R270H/+;Trim28+/D9, Padj = 0.0067860 (F = 9.13); Trim28+/D9 versus Trp53R270H/+, Padj = 0.0025152 (F = 12.126); Trim28+/D9 versus Trp53R270H/+;Trim28+/D9, Padj = 0.8220000 (F = 0.051); Trp53R270H/+;Trim28+/D9 versus Trp53R270H/+, Padj = 0.0067860 (F = 8.5555). n = 130 male mice (16 WT, 35 Trim28+/D9, 41 Trp53R270H/+, 38 Trp53R270H/+;Trim28+/D9). b, Fat and lean mass data at 16 weeks by genotype, with overlaid mclust density estimation. Each dot represents one male; dot size is proportional to mclust classification certainty. n = 138 male mice (18 WT, 36 Trim28+/D9, 43 Trp53R270H/+, 41 Trp53R270H/+;Trim28+/D9). c, Bimodality index: ratio of mclust-determined Bayesian information criterion (BIC) for two clusters over one from fat and lean mass data at 16 weeks. n = 138 male mice (same as in b: 18 WT, 36 Trim28+/D9, 43 Trp53R270H/+, 41 Trp53R270H/+;Trim28+/D9). d, Proportion of Trim28+/D9-heavy and Trim28+/D9-light males with malignant aggressive tumors as a percentage of males per group (before and after endpoint). Actual numbers are given in fractions. Two-sided two-sample test for equality of proportions without continuity correction; significance for P < 0.05: heavy versus light, P = 0.01466, χ2 = 5.9571, degrees of freedom (df) = 1. n = 23 male mice (15 heavy, 8 light). e, Kaplan–Meier survival probability of Trim28+/D9-heavy and Trim28+/D9-light mice. Log-rank test, P = 0.011. n = 23 males (15 heavy, 8 light). f, Prevalence of aggressive tumor types in Trim28+/D9-heavy and Trim28+/D9-light mice as a percentage of total aggressive tumors per group. Actual numbers are shown in fractions. n = 14 tumors (malignant and benign; 3 in heavy and 11 in light). g, Distribution of tumor types in Trim28+/D9-heavy and Trim28+/D9-light mice, as a percentage of mice with malignant aggressive tumors per group. Actual numbers are shown in fractions. Right, age-related carcinoma (red), carcinoma (gold), leukemia (light green). CA, carcinoma; GEJ, gastro-esophageal junction. n = 7 males (2 heavy, 5 light). h, Fraction of Trim28+/D9-heavy and Trim28+/D9-light mice with 0 or multiple malignant aggressive tumors. Actual numbers are shown in fractions. n = 8 males (3 heavy, 5 light). i, Tissues targeted by malignant aggressive tumors by genotype. Top, mouse anatomy plots; nontargeted tissues are in light gray, and targeted tissues are colored by genotype: WT (black), Trim28+/D9 (orange), Trp53R270H/+ (green), Trp53R270H/+;Trim28+/D9 (purple). Bottom, organs with malignant aggressive tumors by morph. n = 7 males (2 heavy, 5 light). j, Histological examples of aggressive malignant tumors in Trim28+/D9-heavy and Trim28+/D9-light mice. Top left, AML, heavy (as in Fig. 2). Top middle, prostatic ACA, light. Top right, seminal vesicle ACA, light. Bottom left, BAC, light. Bottom middle, gastro-esophageal junction SCC, light. Bottom right, colon ACA, light. n = 7 males (2 heavy, 5 light). Panel i, top created with BioRender.com.
