Fig. 4: Pan-cancer DNA methylation correlates of patient survival.
a A top set of 6415 CpG Island (CGI) array probes and a top set of 2397 methylation probes near enhancers were significantly associated with patient survival (both FDR < 10% and nominal p < 0.001, Cox correcting for cancer type) in respective pan-cancer analyses across 8905 cancers. For these probes, heat maps represent the respective associations with patient survival for each individual cancer type. b Top: Fraction of promoter-associated CGIs for the CGI probes, respectively, associated with worse or better patient survival in pan-cancer analyses (from part a). Bottom: Breakdown by probe position relative to the gene for CGI probes associated with worse or better survival, respectively. TSS, transcription start site; UTR, untranslated region. c The CGI survival signature from part (a) was applied to four independent DNA methylation array datasets outside of TCGA (pediatric brain tumors25, ependymoma53, glioblastoma54, and breast55) and was able to stratify patients according to survival outcome. d Overlap between CGI probes with pan-cancer methylation survival association (from part a) and the corresponding genes with pan-cancer mRNA survival association (FDR < 10%). COSMIC57 genes with both CGI methylation associated with better survival and mRNA associated with worse survival are listed by name, with the CGI probe numbers involved. For b and d, enrichment p values by chi-squared test. e For top enhancers with methylation probes associated with pan-cancer survival (from part a), the genes within 500 kb of the enhancer were examined for mRNA survival association (FDR < 10%). Chi-squared tests compare the number of genes with mRNA survival association with the chance expected. f For genes EZH2 (top) and KRAS (bottom), respective associations of mRNA and methylation of nearby enhancer (“ENH”) with patient survival across the TCGA cohort. P values by stratified log-rank test correcting for cancer type.
