Integrative analysis demonstrates widespread NOTCH pathway activation in patients with renal cancer and reveals aberrant DNA methylation that targets the regulatory regions of the kidney genome

ABSTRACT: Even though mutations in epigenetic regulators have been seen in renal neoplasms, their effects on the epigenome have not been elucidated. High resolution analysis of DNA methylation was performed in clear cell RCCs and matched microdissected renal tubular controls and revealed widespread hypermethylation that preferentially affected gene bodies and CpG shores. Aberrant methylation was particularly enriched in kidney specific enhancer regions associated with H3K4Me1 marks. MOTIF analysis of aberrantly methylated loci revealed enrichment for AHR, HAIRY and HIF-1 transcription factors, reflecting dysregulated hypoxia and NOTCH pathways in RCC. Parallel copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in RCC. NOTCH ligands,JAGGED1 and JAGGED2, were overexpressed and associated with hypomethylation and amplification respectively in RCC samples. Examination of TCGA RNA-seq dataset revealed widespread activation of NOTCH pathway in 405 RCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Finally, transgenic expression of NOTCH1 led to dysplastic hyperproliferation of tubular epithelial cells in vivo confirming the procarcinogenic role of NOTCH. In summary, our study is the first global methylome analysis of RCC and reveals that mechanistic basis of NOTCH pathway activation in RCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49420 | GEO | 2014/07/31

SECONDARY ACCESSION(S): PRJNA213865

REPOSITORIES: GEO