Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes

Abstract

Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT.

microRNA-mRNA interaction identification in Wilms tumor using principal component analysis based unsupervised feature extraction

“…After identifying outliers (adjusted P -values < 0.01, see Methods), we have gotten 55 miRNAs and 1114 probes attributed to each mRNA, respectively. One should note that these numbers were much smaller than those identified by Luding et al [3]. Thus, since these are feasible, our methodology has more power to get limited number of critical miRNAs/mRNAs.…”

“…It worked pretty well although it was not modified from samples to samples (from cohorts to cohorts) so as to get feasible results, but employed single common criterion to identify feasible miRNA-mRNA pairs. In this paper, the almost same strategy was applied to data set used by Luding et al [3], and it turned out to work well for these data sets; for example, top 15 down-regulated miRNAs in Wilms tumor compared with normal kidney shown in thier Table 1 were almost identified without optimizing almost anything (no FC threshold, no specified number of top ranked miRNAs, and adjusted Pvalues are used).…”

“…In order to develop the effective therapy, it is critically important to understand how Wilms tumor develops from normal kidney. In this regards, potential role of microRNA(miRNA) in Wilms tumor development recently collected broad interests [3], [4], [5], [6], [7].…”

“…Among those researches, although Luding et al [3] successfully identified feasible miRNA-mRNA pairs, from the methodological point views, there remains some possibilities to be improved. For example, they employed non-adjusted P -values to identify differently expressed miRNA/mRNAs between Wilms tumor and healthy control.…”

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

“…Recent studies with patient samples have used targeted exome sequencing to categorize additional mutations in WT. Apart from the genes that are involved in kidney development, a new category of mutations in the microRNA processing pathway (Wegert et al, 2015, Gadd et al, 2017, Ludwig et al, 2016 was identified.…”