The association between 5mC levels at the TERT promoter and either poorer overall survival in liver cancer and kidney renal papillary cell carcinoma, or significantly improved overall survival in patients with stomach adenocarcinoma, suggests that these epigenotypes may be relevant to cancer progression. Association between higher methylation at cg11625005 and poorer patient survival has been previously reported (Castelo-Branco et al., 2013, 2016; Gojo et al., 2017; Seynnaeve et al., 2017); our results extend these findings to two additional cancer types, suggesting that hypermethylation of the TERT promoter may represent a broadly applicable prognostic marker.
To our knowledge, our data showing a more positive outcome for stomach adenocarcinoma patients with higher methylation at cg11625005 or with high EZH2 expression are novel, and suggest that the mechanisms driving survival in these patients may be distinct.
Stern J.L., Paucek R.D., Huang F.W., Ghandi M., Nwumeh R., Costello J., Cech T.R. Allele-specific DNA methylation and its interplay with repressive histone marks at promoter-mutant TERT genes. Cell Reports (2017). https://doi.org/10.1016/j.celrep.2017.12.001
Identification of genes that correlate with favorable patient prognosis
Cell surface signaling proteins whose gene expression is correlated with improved prognosis may be susceptible to hyperactivation through therapeutic ligand stimulation and may therefore represent viable clinical targets. In liver cancer, the expression of a number of ligand-dependent cell surface signaling proteins correlate with improved prognosis.
Hypermethylation of several CpGs at the some gene transcriptional start sites correlate with lower mRNA expression and poorer survival of urothelial cancer patients. Clustering of 5mC levels and RNAseq data (TCGA) combined with Kaplan-Meier analyses (The Human Protein Atlas) suggest that these genes may be a tumor suppressor repressed by aberrant 5mC deposition. RNAseq and hypermethylation were both independently correlated with patient survival.
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