Fig. 8: Trim28+/D9-light hypomethylated signature genes are associated with reduced survival probability in humans.
a, Left, Kaplan–Meier survival probability as a percentage of the total population and time of survival in months. Log-rank test, P = 1.516 × 10−6. Total samples analyzed, 10,967. Right, Kaplan–Meier disease-free survival probability. Log-rank test, P = 1.27 × 10−9. Left and right, all TCGA Pan-Cancer Atlas patients with mutations in genes from the TRIM28+/D9-light hypomethylated signature (light orange, n = 3,766 samples) are compared to individuals without mutations in the same genes (black, n = 7,180 samples). b, Heatmap of the effects on overall survival probability of mutations in the indicated genes and tumor tissues. The analysis includes all samples from TCGA and non-TCGA studies with no overlapping samples, from cBioPortal (n = 69,223 samples). Tumor tissues are separated in two main branches according to sample number informing the analysis (left, >3,000 samples; right, <3,000 samples). PNS, peripheral nervous system. c, Volcano plot showing the type of interaction for pairwise mutations in genes from the TRIM28+/D9-light hypomethylated signature in all TCGA Pan-Cancer Atlas patients. Red indicates co-occurrence, and blue indicates mutual exclusivity of pairwise mutations. One-sided Fisher’s exact test, Benjamini–Hochberg Padj cutoff = 0.05. Total samples analyzed, 10,967. d, Our model suggests that TRIM28 buffers intrinsic developmental heterogeneity via heterochromatin silencing. By modulating a differentially methylated cancer-related gene set, it primes two distinct developmental trajectories for cancer susceptibility and outcomes, with one of the trajectories being more resistant and the other prone to cancer. Created with BioRender.com.
