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Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis

ABSTRACT: Renal cell carcinoma (RCC) is among the ten most common malignancies. By far, the most common histology is clear cell (ccRCC). The Cancer Genome Atlas and other large scale sequencing studies of ccRCC have been integral to the current understanding of molecular events underlying RCC and its biology. However, these data sets have focused on primary RCC which often demonstrates indolent behavior. In contrast, metastatic disease is the major cause of mortality associated with ccRCC. However, data sets examining metastatic tumor are sparse. We therefore undertook an integrative analysis of gene expression and DNA methylome profiling of metastatic ccRCC in addition to primary RCC and normal kidney. Integrative analysis of the methylome and transcriptome identified over 30 RCC specific genes whose mRNA expression inversely correlated with promoter methylation including several known targets of hypoxia inducible factors (HIFs). Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation. Collectively, our data provide novel insight into biology of aggressive RCC. Furthermore, they demonstrate a clear role for epigenetics in the promotion of HIF signaling and invasive phenotypes in renal cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE105288 | GEO | 2018/10/16

REPOSITORIES: GEO

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Project description:Background/Objective: MicroRNAs (miRNAs) play a pivotal role in cancerogenesis and cancer progression, but their specific role in metastasis of clear cell renal cell carcinomas (ccRCCs) as so-called metastamirs is still limited. Based on microRNA microarray analyses from normal (n=12) and cancerous (n=12) samples of ccRCC specimens and from bone metastases (n=9) of ccRCC patients, we identified a set of 57 differentially expressed microRNAs between those three sample groups of ccRCC. A selected panel of 33 miRNAs, including miRNAs reported in the literature as differentially expressed in non-metastatic RCC, was validated by RT-qPCR on 57 clinical samples. 30 of the 33 examined miRNAs were confirmed to be deregulated. A stepwise down-regulated miRNA expression from normal over primary tumor to metastatic tissue samples was found to be typical. 23 miRNAs (miR-10b/-19a/-19b/-20a/-29a/-29b/-29c/-100/-101/-126/-127/-130/-141/-143/-145/-148a/-192/-194/-200c/-210/-215/-370/-514) were down-regulated in metastatic tissue samples in comparison to normal tissue. This down-regulated expression in metastatic tissue was also present in 21 miRNAs except for miR-127 and miR-370. The altered miRNA profiles including the newly identified metastasis-associated miRNAs, the compiled predicted miRNA-target interactions, and the significant correlations of miRNAs which were either lost or newly appeared in the studied sample groups afford a solid basis for further functional analyses of individual miRNAs. In this study, microarray-based profiling was performed from 9 bone metastatic tissue samples from 9 patients with clear cell renal cell carcinoma (ccRCC). For controls, 2 bone metastatic samples from two patients with prostate carcinoma and 5 total RNA pools (2 different pools of total RNAs isolated from malignant renal tissue samples derived from different ccRCC patients; 1 pool from non-malignant renal tissue of ccRCC patients; 2 pools of total RNA both from malignant and non-malignant prostate cancer tissue) were used. In addition, matched malignant (e.g., malignant NC2) and non-malignant (e.g., non-malignant NN1) samples from two independent 12 ccRCC sets were profiled (these samples were previously analyzed on a different Platform in GSE12105). The 2002 TNM System and the 2004 WHO classification was used for staging and grading.

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Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis

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