Abstract
A novel integrative pipeline is presented for discovery of potential cancer-susceptibility regions (PCSRs) by calculating the number of altered genes at each chromosomal region, using expression microarray datasets of different human cancers (HCs). Our novel approach comprises primarily predicting PCSRs followed by identification of key genes in these regions to obtain potential regions harboring new cancer-associated variants. In addition to finding new cancer causal variants, another advantage in prediction of such risk regions is simultaneous study of different types of genomic variants in line with focusing on specific chromosomal regions. Using this pipeline we extracted numbers of regions with highly altered expression levels in cancer condition. Regulatory networks were also constructed for different types of cancers following the identification of altered mRNA and microRNAs. Interestingly, results showed that GAPDH, LIFR, ZEB2, mir-21, mir-30a, mir-141 and mir-200c, all located at PCSRs, are common altered factors in constructed networks. We found a number of clusters of altered mRNAs and miRNAs on predicted PCSRs (e.g.12p13.31) and their common regulators including KLF4 and SOX10. Large scale prediction of risk regions based on transcriptome data can open a window in comprehensive study of cancer risk factors and the other human diseases.
Highlights
Alteration in mRNAs and miRNAs expression and the important role of a large number of these molecules have been studied in the initiation, progression and metastasis of many types of cancers [1,2,3]_ENREF_1
Changes in DNA methylation and transcription factor (TF) regulation, genomic copy number variation (CNV) [4], single nucleotide polymorphism (SNP) [5] and microsatellite alternation [6] as well as other chromosomal aberrations are characterized as major mechanisms of expression alternation in different human cancers (HCs)
These altered RNAs including mir-141, mir-200c and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Zinc finger E-box binding homeobox 2 (ZEB2) are all located at predicted Potential Cancer-Susceptibility Region. Symbols (PCSR)
Summary
Alteration in mRNAs and miRNAs expression and the important role of a large number of these molecules have been studied in the initiation, progression and metastasis of many types of cancers [1,2,3]_ENREF_1. Gene expression data of several types of cancers were reanalyzed and the results were combined to predict common cancer-risk regions Another aim of this study was to obtain insight into interrelation between PCSRs and altered mRNAs, miRNAs and their common regulators. Mir-141 and, mir-200c, which were over-expressed in 3 HCs (shown as purple in the Figure 3), have miRNA effects on ZEB2 (with down-expression in 7 HCs) These altered RNAs including mir-141, mir-200c and GAPDH (at 12p13.31) and ZEB2 (at 2q22.3) are all located at predicted PCSRs. In the case of upstream nodes, TP53 and MYC were observed as upstream regulators of mir-200c and GAPDH (Figure 3). GATA2 was predicted for both down-expressed mRNAs and altered miRNAs
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