Pan-cancer antagonistic inhibition pattern of ATM-driven G2/M checkpoint pathway vs other DNA repair pathways.

DNA repair mechanisms keep genome integrity and limit tumor-associated alterations and heterogeneity, but on the other hand they promote tumor survival after radiation and genotoxic chemotherapies. We screened pathway activation levels of 38 DNA repair pathways in nine human cancer types (gliomas, breast, colorectal, lung, thyroid, cervical, kidney, gastric, and pancreatic cancers). We took RNAseq profiles of the experimental 51 normal and 408 tumor samples, and from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases - of 500/407 normal and 5752/646 tumor samples, and also 573 normal and 984 tumor proteomic profiles from Proteomic Data Commons portal. For all the samplings we observed a congruent trend that all cancer types showed inhibition of G2/M arrest checkpoint pathway compared to the normal samples, and relatively low activities of p53-mediated pathways. In contrast, other DNA repair pathways were upregulated in most of the cancer types. The G2/M checkpoint pathway was statistically significantly downregulated compared to the other DNA repair pathways, and this inhibition was strongly impacted by antagonistic regulation of (i) promitotic genes CCNB and CDK1, and (ii) GADD45 genes promoting G2/M arrest. At the DNA level, we found that ATM, TP53, and CDKN1A genes accumulated loss of function mutations, and cyclin B complex genes - transforming mutations. These findings suggest importance of activation for most of DNA repair pathways in cancer progression, with remarkable exceptions of G2/M checkpoint and p53-related pathways which are downregulated and neutrally activated, respectively.

OncoboxPD: human 51 672 molecular pathways database with tools for activity calculating and visualization.

OncoboxPD (Oncobox pathway databank) available at https://open.oncobox.com is the collection of 51 672 uniformly processed human molecular pathways. Superposition of all pathways formed interactome graph of protein-protein interactions and metabolic reactions containing 361 654 interactions and 64 095 molecular participants. Pathways are uniformly classified by biological processes, and each pathway node is algorithmically functionally annotated by specific activator/repressor role. This enables online calculation of statistically supported pathway activation levels (PALs) with the built-in bioinformatic tool using custom RNA/protein expression profiles. Each pathway can be visualized as static or dynamic graph, where vertices are molecules participating in a pathway and edges are interactions or reactions between them. Differentially expressed nodes in a pathway can be visualized in two-color mode with user-defined color scale. For every comparison, OncoboxPD also generates a graph summarizing top up- and downregulated pathways.

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology.

Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions. Here, we compared interpatient molecular heterogeneities of tumors and repertoires of drugs or their molecular targets currently in use in clinical oncology. We estimated molecular heterogeneity using genomic (whole exome sequencing) and transcriptomic (RNA sequencing) data for 4890 tumors taken from The Cancer Genome Atlas database. For thirteen major cancer types, we compared heterogeneities at the levels of mutations and gene expression with the repertoires of targeted therapeutics and their molecular targets accepted by the current guidelines in oncology. Totally, 85 drugs were investigated, collectively covering 82 individual molecular targets. For the first time, we showed that the repertoires of molecular targets of accepted drugs did not correlate with molecular heterogeneities of different cancer types. On the other hand, we found that the clinical recommendations for the available cancer drugs were strongly congruent with the gene expression but not gene mutation patterns. We detected the best match among the drugs usage recommendations and molecular patterns for the kidney, stomach, bladder, ovarian and endometrial cancers. In contrast, brain tumors, prostate and colorectal cancers showed the lowest match. These findings provide a theoretical basis for reconsidering usage of targeted therapeutics and intensifying drug repurposing efforts.

Pathway Based Analysis of Mutation Data Is Efficient for Scoring Target Cancer Drugs.

Despite the significant achievements in chemotherapy, cancer remains one of the leading causes of death. Target therapy revolutionized this field, but efficiencies of target drugs show dramatic variation among individual patients. Personalization of target therapies remains, therefore, a challenge in oncology. Here, we proposed molecular pathway-based algorithm for scoring of target drugs using high throughput mutation data to personalize their clinical efficacies. This algorithm was validated on 3,800 exome mutation profiles from The Cancer Genome Atlas (TCGA) project for 128 target drugs. The output values termed Mutational Drug Scores (MDS) showed positive correlation with the published drug efficiencies in clinical trials. We also used MDS approach to simulate all known protein coding genes as the putative drug targets. The model used was built on the basis of 18,273 mutation profiles from COSMIC database for eight cancer types. We found that the MDS algorithm-predicted hits frequently coincide with those already used as targets of the existing cancer drugs, but several novel candidates can be considered promising for further developments. Our results evidence that the MDS is applicable to ranking of anticancer drugs and can be applied for the identification of novel molecular targets.

Friends-Enemies: Endogenous Retroviruses Are Major Transcriptional Regulators of Human DNA.

Endogenous retroviruses are mobile genetic elements hardly distinguishable from infectious, or "exogenous," retroviruses at the time of insertion in the host DNA. Human endogenous retroviruses (HERVs) are not rare. They gave rise to multiple families of closely related mobile elements that occupy ~8% of the human genome. Together, they shape genomic regulatory landscape by providing at least ~320,000 human transcription factor binding sites (TFBS) located on ~110,000 individual HERV elements. The HERVs host as many as 155,000 mapped DNaseI hypersensitivity sites, which denote loci active in the regulation of gene expression or chromatin structure. The contemporary view of the HERVs evolutionary dynamics suggests that at the early stages after insertion, the HERV is treated by the host cells as a foreign genetic element, and is likely to be suppressed by the targeted methylation and mutations. However, at the later stages, when significant number of mutations has been already accumulated and when the retroviral genes are broken, the regulatory potential of a HERV may be released and recruited to modify the genomic balance of transcription factor binding sites. This process goes together with further accumulation and selection of mutations, which reshape the regulatory landscape of the human DNA. However, developmental reprogramming, stress or pathological conditions like cancer, inflammation and infectious diseases, can remove the blocks limiting expression and HERV-mediated host gene regulation. This, in turn, can dramatically alter the gene expression equilibrium and shift it to a newer state, thus further amplifying instability and exacerbating the stressful situation.

Early stage of cytomegalovirus infection suppresses host microRNA expression regulation in human fibroblasts.

Responses to human cytomegalovirus (HCMV) infection are largely individual and cell type specific. We investigated molecular profiles in 2 primary cell cultures of human fibroblasts, which are highly or marginally sensitive to HCMV infection, respectively. We screened expression of genes and microRNAs (miRs) at the early (3 hours) stage of infection. To assess molecular pathway activation profiles, we applied bioinformatic algorithms OncoFinder and MiRImpact. In both cell types, pathway regulation properties at mRNA and miR levels were markedly different. Surprisingly, in the infected highly sensitive cells, we observed a "freeze" of miR expression profiles compared to uninfected controls. Our results evidence that in the sensitive cells, HCMV blocks intracellular regulation of microRNA expression already at the earliest stage of infection. These data suggest somewhat new functions for HCMV products and demonstrate dependence of miR expression arrest on the host-encoded factors.

A systematic experimental evaluation of microRNA markers of human bladder cancer.

BACKGROUND: MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression. They are aberrantly expressed in many human cancers and are potential therapeutic targets and molecular biomarkers. METHODS: In this study, we for the first time validated the reported data on the entire set of published differential miRNAs (102 in total) through a series of transcriptome-wide experiments. We have conducted genome-wide miRNA profiling in 17 urothelial carcinoma bladder tissues and in nine normal urothelial mucosa samples using three methods: (1) An Illumina HT-12 microarray hybridization (MA) analysis (2) a suppression-subtractive hybridization (SSH) assay followed by deep sequencing (DS) and (3) DS alone. RESULTS: We show that DS data correlate with previously published information in 87% of cases, whereas MA and SSH data have far smaller correlations with the published information (6 and 9% of cases, respectively). qRT-PCR tests confirmed reliability of the DS data. CONCLUSIONS: Based on our data, MA and SSH data appear to be inadequate for studying differential miRNA expression in the bladder. IMPACT: We report the first comprehensive validated database of miRNA markers of human bladder cancer.

Characteristic patterns of microRNA expression in human bladder cancer.

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression. Their altered expression and functional activity have been observed in many human cancers. miRNAs represent promising diagnostic and prognostic molecular biomarkers, and also serve as novel therapeutic targets. We performed a systematic analysis of scientific reports that link differences in miRNA expression with the pathogenesis of bladder cancer (BC). This literature review is the first comprehensive database of miRNA molecules with biased expression profiles in BC. Among the 95 differentially expressed miRNAs that we identified from the literature, we classify 48 as up-regulated in BC, 35 as down-regulated, and 12 as contradictory (contradictory data were reported in one or more studies on the gene). In addition, we discuss the possible roles of differentially expressed miRNAs in the regulation of intracellular signaling pathways in BC.