Genome-Wide Promoter Methylome of Small Renal Masses

Abstract

The majority of renal cell carcinoma (RCC) is now incidentally detected and presents as small renal masses (SRMs) defined as ≤4 cm in size. SRMs are heterogeneous comprising several histological types of RCC each with different biology and behavior, and benign tumors mainly oncocytoma. The varied prognosis of the different types of renal tumor has implications for management options. A key epigenetic alteration involved in the initiation and progression of cancer is aberrant methylation in the promoter region of a gene. The hypermethylation is associated with transcriptional repression and is an important mechanism of inactivation of tumor suppressor genes in neoplastic cells. We have determined the genome-wide promoter methylation profiles of 47 pT1a and 2 pT1b clear cell, papillary or chromophobe RCC, 25 benign renal oncocytoma ≤4 cm and 4 normal renal parenchyma specimens by Infinium HumanMethylation27 beadchip technology. We identify gene promoter hypermethylation signatures that distinguish clear cell and papillary from each other, from chromophobe and oncocytoma, and from normal renal cells. Pairwise comparisons revealed genes aberrantly hypermethylated in a tumor type but unmethylated in normal, and often unmethylated in the other renal tumor types. About 0.4% to 1.7% of genes comprised the promoter methylome in SRMs. The Infinium methylation score for representative genes was verified by gold standard technologies. The genes identified as differentially methylated implicate pathways involved in metabolism, tissue response to injury, epithelial to mesenchymal transition (EMT), signal transduction and G-protein coupled receptors (GPCRs), cancer, and stem cell regulation in the biology of RCC. Our findings contribute towards an improved understanding of the development of RCC, the different biology and behavior of histological types, and discovery of molecular subtypes. The differential methylation signatures may have utility in early detection and particularly differential diagnosis for prognostic stratification as well as identify novel gene and pathway targets for therapeutic intervention.

A global profile of gene promoter methylation in treatment-naïve urothelial cancer

“…We chose this cut-off because Illumina has reported that β < 0.15 can be due to the background noise of the assay chemistry at the unmethylated state 15 . In addition, we have found probes with β < 0.15 to typically read as unmethylated (0%) by pyrosequencing of the identical CpG loci 16 . We used the Wilcoxon Rank sum test in a two-group comparison with a P value < 0.05 as significant.…”

Hypoxia-inducible factors enhance glutamate signaling in cancer cells

“…In contrast, GRIK2 , which is the gene most frequently involved in chromosome 6q deletions in acute lymphocytic leukemia, is regarded as a tumor suppressor gene [ 28 ]. Additionally, hypermethylation of GRIK1 , GRIK2 , GRIN2A and GRIN2B has been reported in ccRCC, gastric cancer, colon cancer, esophageal squamous cell carcinoma and NSCLC [ 29 - 34 ]. Thus, the effect of gain or loss of glutamate receptor function varies in different cancers.…”

Improving needle biopsy accuracy in small renal mass using tumor-specific DNA methylation markers

“…There have been previous reports that have found DNA methylation biomarkers specific for clear cell but provide limited data on other subtypes of RCC and benign tumors [24–26]. In our study, we provide detailed methylation profiling of subtypes of benign phenotypes, which we developed from microdissection of FFPE tissue from kidney cases resected at the University of Southern California.…”