Integrative Genome-Wide Gene Expression Profiling of Clear Cell Renal Cell Carcinoma in Czech Republic and in the United States

Abstract

Gene expression microarray and next generation sequencing efforts on conventional, clear cell renal cell carcinoma (ccRCC) have been mostly performed in North American and Western European populations, while the highest incidence rates are found in Central/Eastern Europe. We conducted whole-genome expression profiling on 101 pairs of ccRCC tumours and adjacent non-tumour renal tissue from Czech patients recruited within the “K2 Study”, using the Illumina HumanHT-12 v4 Expression BeadChips to explore the molecular variations underlying the biological and clinical heterogeneity of this cancer. Differential expression analysis identified 1650 significant probes (fold change ≥2 and false discovery rate <0.05) mapping to 630 up- and 720 down-regulated unique genes. We performed similar statistical analysis on the RNA sequencing data of 65 ccRCC cases from the Cancer Genome Atlas (TCGA) project and identified 60% (402) of the downregulated and 74% (469) of the upregulated genes found in the K2 series. The biological characterization of the significantly deregulated genes demonstrated involvement of downregulated genes in metabolic and catabolic processes, excretion, oxidation reduction, ion transport and response to chemical stimulus, while simultaneously upregulated genes were associated with immune and inflammatory responses, response to hypoxia, stress, wounding, vasculature development and cell activation. Furthermore, genome-wide DNA methylation analysis of 317 TCGA ccRCC/adjacent non-tumour renal tissue pairs indicated that deregulation of approximately 7% of genes could be explained by epigenetic changes. Finally, survival analysis conducted on 89 K2 and 464 TCGA cases identified 8 genes associated with differential prognostic outcomes. In conclusion, a large proportion of ccRCC molecular characteristics were common to the two populations and several may have clinical implications when validated further through large clinical cohorts.

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

“…Lastly, an examination of somatically altered superenhancers enabled us to identify a master regulator crucial to the pathogenesis of ccRCC, ZNF395. Even though ZNF395 overexpression in ccRCC has been previously reported (79)(80)(81) and its proximity to a superenhancer was independently noted (42), our study is the first to pinpoint the specific VHL-dependent enhancer required for ZNF395 expression and to show ZNF395's indispensable functional role for ccRCC tumorigenesis in vitro and in vivo.…”

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

“…According to recent reports, higher CLEC14A expression is directly associated with longer survival of patients with aggressive carcinomas such as clear-cell renal cell carcinoma and non-small-cell lung carcinoma (40,41). This favorable clinical…”

Genome-wide methylation analysis of tubulocystic and papillary renal cell carcinomas

“…Similar results were obtained when the clear cell renal carcinomas were compared with adjacent non-tumorous tissues. Deregulation of approximately 7% genes was explained by epigenetic changes in this case [15].…”

“…With regard to renal carcinogenesis, few studies concerning differential methylation were published using different array platforms [15,17,18] and no study has been focused on alteration of promoter methylation in TRCC.…”