CpG island methylator phenotype (CIMP) is found in 15–20% of malignant colorectal tumors and is characterized by strong CpG hypermethylation over the genome. The molecular mechanisms of this phenomenon are not still fully understood. The development of CIMP is followed by global gene expression alterations and metabolic changes. In particular, CIMP-low colon adenocarcinoma (COAD), predominantly corresponded to consensus molecular subtype 3 (CMS3, “Metabolic”) subgroup according to COAD molecular classification, is associated with elevated expression of genes participating in metabolic pathways. We performed bioinformatics analysis of RNA-Seq data from The Cancer Genome Atlas (TCGA) project for CIMP-high and non-CIMP COAD samples with DESeq2, clusterProfiler, and topGO R packages. Obtained results were validated on a set of fourteen COAD samples with matched morphologically normal tissues using quantitative PCR (qPCR). Upregulation of multiple genes involved in glycolysis and related processes (ENO2, PFKP, HK3, PKM, ENO1, HK2, PGAM1, GAPDH, ALDOA, GPI, TPI1, and HK1) was revealed in CIMP-high tumors compared to non-CIMP ones. Most remarkably, the expression of the PKLR gene, encoding for pyruvate kinase participating in gluconeogenesis, was decreased approximately 20-fold. Up to 8-fold decrease in the expression of OGDHL gene involved in tricarboxylic acid (TCA) cycle was observed in CIMP-high tumors. Using qPCR, we confirmed the increase (4-fold) in the ENO2 expression and decrease (2-fold) in the OGDHL mRNA level on a set of COAD samples. We demonstrated the association between CIMP-high status and the energy metabolism changes at the transcriptomic level in colorectal adenocarcinoma against the background of immune pathway activation. Differential methylation of at least nine CpG sites in OGDHL promoter region as well as decreased OGDHL mRNA level can potentially serve as an additional biomarker of the CIMP-high status in COAD.

Currently, seven molecular subtypes of prostate cancer (PCa) are known, the most common of which being the subtype characterized by the presence of the TMPRSS2–ERG fusion transcript. While there is a considerable amount of work devoted to the influence of this transcript on the prognosis of the disease, data on its role in the progression and prognosis of PCa remain controversial. The present study is devoted to the analysis of the association between the TMPRSS2–ERG transcript and the biochemical recurrence of PCa. The study included two cohorts: the RNA–Seq sample of Russian patients with PCa (n = 72) and the TCGA–PRAD data (n = 203). The results of the analysis of the association between the TMPRSS2–ERG transcript and biochemical recurrence were contradictory. The differential expression analysis (biochemical recurrence cases versus biochemical recurrence-free) and the gene set enrichment analysis revealed a list of genes involved in major cellular pathways. The GNL3, QSOX2, SSPO, and SYS1 genes were selected as predictors of the potential prognostic model (AUC = 1.000 for a cohort of Russian patients with PCa and AUC = 0.779 for a TCGA–PRAD cohort).

Castration-resistant prostate cancer (CRPC) is a common form of prostate cancer in which docetaxel-based chemotherapy is used as the first line. The present study is devoted to the analysis of transcriptome profiles of tumor cells in the development of resistance to docetaxel as well as to the assessment of the combined effect with the XAV939 tankyrase inhibitor on maintaining the sensitivity of tumor cells to chemotherapy. RNA-Seq was performed for experimental PC3 cell lines as well as for plasma exosome samples from patients with CRPC. We have identified key biological processes and identified a signature based on the expression of 17 mRNA isoforms associated with the development of docetaxel resistance in PC3 cells. Transcripts were found in exosome samples, the increased expression of which was associated with the onset of progression of CRPC during therapy. The suppression of pathways associated with the participation of cellular microtubules has also been shown when cells are treated with docetaxel in the presence of XAV939. These results highlight the importance of further research into XAV939 as a therapeutic agent in the treatment of CRPC; moreover, we have proposed a number of mRNA isoforms with high predictive potential, which can be considered as promising markers of response to docetaxel.

Molecular heterogeneity in prostate cancer (PCa) is one of the key reasons underlying the differing likelihoods of recurrence after surgical treatment in individual patients of the same clinical category. In this study, we performed RNA-Seq profiling of 58 localized PCa and 43 locally advanced PCa tissue samples obtained as a result of radical prostatectomy on a cohort of Russian patients. Based on bioinformatics analysis, we examined features of the transcriptome profiles within the high-risk group, including within the most commonly represented molecular subtype, TMPRSS2-ERG. The most significantly affected biological processes in the samples were also identified, so that they may be further studied in the search for new potential therapeutic targets for the categories of PCa under consideration. The highest predictive potential was found with the EEF1A1P5, RPLP0P6, ZNF483, CIBAR1, HECTD2, OGN, and CLIC4 genes. We also reviewed the main transcriptome changes in the groups at intermediate risk of PCa—Gleason Score 7 (groups 2 and 3 according to the ISUP classification)—on the basis of which the LPL, MYC, and TWIST1 genes were identified as promising additional prognostic markers, the statistical significance of which was confirmed using qPCR validation.

Following radical surgery, patients may suffer a relapse. It is important to identify such patients so that therapy tactics can be modified appropriately. Existing stratification schemes do not display the probability of recurrence with enough precision since locally advanced prostate cancer (PCa) is classified as high-risk but is not ranked in greater detail. Between 40 and 50% of PCa cases belong to the TMPRSS2-ERG subtype that is a sufficiently homogeneous group for high-precision prognostic marker search to be possible. This study includes two independent cohorts and is based on high throughput sequencing and qPCR data. As a result, we have been able to suggest a perspective-trained model involving a deep neural network based on both qPCR data for mRNA and miRNA and clinicopathological criteria that can be used for recurrence risk forecasts in patients with TMPRSS2-ERG-positive, locally advanced PCa (the model uses ALDH3A2 + ODF2 + QSOX2 + hsa-miR-503-5p + ISUP + pT, with an AUC = 0.944). In addition to the prognostic model’s use of identified differentially expressed genes and miRNAs, miRNA–target pairs were found that correlate with the prognosis and can be presented as an interactome network.

BackgroundCarotid body tumor (CBT) is a rare neoplasm arising from paraganglion located near the bifurcation of the carotid artery. There is great intra-tumor heterogeneity, and CBT development could be associated with both germline and somatic allelic variants. Studies on the molecular genetics of CBT are limited, and the molecular mechanisms of its pathogenesis are not fully understood. This work is focused on the estimation of mutational load (ML) in CBT.MethodsUsing the NextSeq 500 platform,we performed exome sequencing of tumors with matched lymph node tissues and peripheral blood obtained from six patients with CBT. To obtain reliable results in tumors withlow ML, we developed and successfully applied a complex approach for the analysis of sequencing data. ML was evaluated as the number of somatic variants per megabase (Mb) of the target regions covered by the Illumina TruSeq Exome Library Prep Kit.ResultsThe ML in CBT varied in the range of 0.09-0.28/Mb. Additionally, we identified several pathogenic/likely pathogenic somatic and germline allelic variants across six patients studied (including TP53 variants).ConclusionsUsing the developed approach, we estimated the ML in CBT, which is much lower than in common malignant tumors. Identified variants in known paraganglioma/pheochromocytoma-causative genes and novel genescouldbe associated with thepathogenesis of CBT. The obtained results expand ourknowledgeof the mutationprocess in CBTas well as the biology of tumor development.