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Genomic and transcriptomic data integration and its automated analysis in clear-cell renal cell carcinoma suggests population heterogeneity of causes and mechanism of the disease

ABSTRACT: Renal cell carcinoma (RCC) is one of the most widespread solid kidney tumors – it represents 90% of all malignant kidney tumors. Clear-cell RCC is the most widespread type of RCC. It is characterized by 3-rd chromosome rearrangements, VHL inactivation due to mutations or promoter hypermethylation, 5p amplification, and mutations in KDM6A/UTX, SETD2, KDM5C/JARID1C and MLL2 genes. Molecular profile of ccRCC was characterized in a number of research papers using high-throughput platforms (microarray SNP-profiling, RNA-seq, whole exome and whole genome sequencing). Nevertheless, differences of observed mutations and gene expression levels among different populations suggest that causes and mechanism of the disease can also vary. In order to obtain such information about Western Russian population we have performed DNA resequencing and microarray expression profiling, and then integrated this data in a single dataset. We then analyzed DNA mutations and gene expression level simultaneously using standard molecular data analysis pipelines (gene set enrichment analysis, casual gene network generation, principle component analysis).

ORGANISM(S): Homo sapiens

PROVIDER: GSE76351 | GEO | 2015/12/28

SECONDARY ACCESSION(S): PRJNA307068

REPOSITORIES: GEO

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Project description:Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) (collectively, over 70% of all lymphoma diagnoses), these mutations are highly recurrent and appear early during transformation, possibly in pre-malignant precursors. Here we show that FL- and DLBCL-associated MLL2 mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in normal germinal-center (GC) B cells and DLBCL, consistent with the enrichment of MLL2 binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Mll2 early during B cell development, but not after initiation of the GC reaction, leads to increased percentages and numbers of GC B cells, which feature a distinct transcriptional profile defined by the enrichment of cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Mll2-deficient B cells exhibit proliferative advantage and accumulation in the S phase of the cell cycle, which is influenced by the number of cell divisions. While GC-specific loss of Mll2 was not sufficient to initiate malignant transformation, compound Mll2-deficient/BCL2-transgenic mice displayed an increased incidence of clonal lymphoproliferations resembling the features of human FL and DLBCL. These findings suggest that early MLL2 loss favors BCL2-induced lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of MLL2-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events. Murine germinal center B cells (B220+CD95+PNA+) were sorted from the spleen of conditional Mll2 knock-out, Mll2 heterozygous and Mll2 wild type mice (crossed with CD19-Cre or Cg1-Cre deletor strains) and sacrificed at day 12 after immunization with sheep red blood cells (SRBC)(n=3 mice per genotype). Total RNA was extracted from single cell suspensions and processed according to the Ovation RNA Amplification System and Encore® Biotin Module protocols (both from NuGEN). Samples were analyzed on Affymetrix Mouse Genome 430 2.0 arrays.

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Genomic and transcriptomic data integration and its automated analysis in clear-cell renal cell carcinoma suggests population heterogeneity of causes and mechanism of the disease

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