BACKGROUND: The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown. METHODS: TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays. RESULTS: High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth. CONCLUSION: TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.

• MeSH
• Gene Knockdown Techniques MeSH
• Glioma * pathology   genetics   drug therapy   metabolism   MeSH
• Kruppel-Like Factor 4 MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * genetics   pathology   MeSH
• Lomustine * pharmacology   therapeutic use   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms * pathology   genetics   drug therapy   metabolism   MeSH
• Tumor Necrosis Factor Receptor-Associated Peptides and Proteins * genetics   metabolism   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Cell Proliferation MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Cellular Senescence * drug effects   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Chemoresistance poses one of the most significant challenges of cancer therapy. Carboplatin (CbPt) is one of the most used chemotherapeutics in ovarian cancer (OVC) treatment. MRE11 constitutes a part of homologous recombination (HR), which is responsible for the repair of CbPt-induced DNA damage, particularly DNA crosslinks. The study's main aim was to address the role of HR in CbPt chemoresistance in OVC and to evaluate the possibility of overcoming CbPt chemoresistance by Mirin-mediated MRE11 inhibition in an OVC cell line. Lower expression of MRE11 was associated with better overall survival in a cohort of OVC patients treated with platinum drugs (TCGA dataset, P < 0.05). Using in vitro analyses, we showed that the high expression of HR genes drives the CbPt chemoresistance in our CbPt-resistant cell line model. Moreover, the HR inhibition by Mirin not only increased sensitivity to carboplatin (P < 0.05) but also rescued the sensitivity in the CbPt-resistant model (P < 0.05). Our results suggest that MRE11 inhibition with Mirin may represent a promising way to overcome OVC resistance. More therapy options will ultimately lead to better personalized cancer therapy and improvement of patients' survival.

• MeSH
• Drug Resistance, Neoplasm * genetics   drug effects   MeSH
• MRE11 Homologue Protein * genetics   MeSH
• Carboplatin * pharmacology   therapeutic use   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Ovarian Neoplasms * drug therapy   genetics   MeSH
• DNA Damage drug effects   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Recombinational DNA Repair * drug effects   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Analýza molekulárních biomarkerů umožňujících predikci reakce nádorů na léčbu a zavedení optimální metody pro jejich sledování představují zásadní výzvy současného translačního výzkumu. Tento projekt má za cíl prozkoumat využitelnost metody sekvenování příští generace pro hledání genetických biomarkerů, specifických pro českou populaci, které by umožnily rozdělení pacientů se solidními nádory do prognosticky významných skupin. V rámci projektu bude studován genetický profil pacientů se solidními nádory léčenými adjuvantní terapií režimy založenými na nukleosidových analozích, taxanech a platinových derivátech. Metoda celoexomového sekvenování bude poprvé použita ke studiu tohoto fenoménu u českých pacientů s malignitami. Výsledky studie budou porovnány s daty ve veřejně dostupných databázích, např. TCGA, ICGC a s výstupy projektu NCLG, který mapuje genetickou variabilitu obecné české populace. Hlavním výstupem projektu bude validovaný panel zárodečných variant a somaticky významných genů pro další studie a analýza účinnosti panelového sekvenování, ve srovnání s celoexomovým přístupem.; Search for molecular biomarkers enabling prediction of cancer treatment efficacy and establishment of optimal method for their assessment represent major opportunities, but also challenges in translational research. This project aims to explore feasibility of the next generation sequencing method for discovery of Czech population-specific genetic biomarkers for stratification of cancer patients into prognostically meaningful groups. Genetic background of patients treated with adjuvant chemotherapy regimens based on nucleoside analogs, taxanes and platinum derivatives will be explored by whole exome profiling method in cancer patients of Czech origin for the first time. Results will be compared with data in publicly available databases as TCGA and ICGC and with data from Czech NCGM genetic variability project. Panel of germline variants and somatically relevant genes for prognostication of patients will subsequently be validated and its cost efficacy and benefit will be evaluated in comparison with the whole exome approach.

• Keywords
• prognosis, sekvenování nové generace, Next generation sequencing, therapy, nádor, cancer, terapie, proveditelnost, feasibility, prognoza,

• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND/AIM: The management of patients with clear cell renal cell carcinoma (ccRCC) includes prognosis assessment based on TNM classification and biochemical markers. This approach stratifies patients with advanced ccRCC into groups of favorable, intermediate, and poor prognosis. The aim of the study was to improve prognosis estimation using microRNAs involved in the pathogenesis of ccRCC. PATIENTS AND METHODS: The study was based on a histologically-verified set of matched ccRCC FFPE tissue samples (normal renal tissue, primary tumor, metastasis, n=20+20+20). The expression of 2,549 microRNAs was analyzed using the SurePrint G3 Human miRNA microarray kit (Agilent Technologies). Prognostic value of significantly deregulated microRNAs was further evaluated on microRNA expression and clinical data of 475 patients obtained from TCGA Kidney Clear Cell Carcinoma (KIRC) database. RESULTS: There were 13 up-regulated and 6 down-regulated microRNAs in tumor tissues compared to control tissues. Among them, survival analysis revealed those with prognostic significance. Patients with high expression of miR-21, miR-27a, miR-34a, miR-106b, miR-210, and miR-342 showed significantly unfavorable outcome. The opposite was observed for miR-30e, patients with low expression had significantly shorter survival. CONCLUSION: The inclusion of these microRNAs in a prognostic panel holds the potential to enhance stratification scoring systems, on which the treatment of ccRCC patients is based.

• MeSH
• Adult MeSH
• Kaplan-Meier Estimate MeSH
• Carcinoma, Renal Cell * genetics   pathology   mortality   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• MicroRNAs * genetics   MeSH
• Biomarkers, Tumor * genetics   MeSH
• Kidney Neoplasms * genetics   pathology   mortality   metabolism   MeSH
• Prognosis MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Gene Expression Profiling * MeSH
• Up-Regulation MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Non-small cell lung cancer (NSCLC) has been marked as the major cause of death in lung cancer patients. Due to tumor heterogeneity, mutation burden, and emerging resistance against the available therapies in NSCLC, it has been posing potential challenges in the therapy development. Hence, identification of cancer-driving mutations and their effective inhibition have been advocated as a potential approach in NSCLC treatment. Thereof, this study aims to employ the genomic and computational-aided integrative drug repositioning strategy to identify the potential mutations in the selected molecular targets and repurpose FDA-approved drugs against them. Accordingly, molecular targets and their mutations, i.e., EGFR (V843L, L858R, L861Q, and P1019L) and ROS1 (G1969E, F2046Y, Y2092C, and V2144I), were identified based on TCGA dataset analysis. Following, virtual screening and redocking analysis, Elbasvir, Ledipasvir, and Lomitapide drugs for EGFR mutants (>-10.8 kcal/mol) while Indinavir, Ledipasvir, Lomitapide, Monteleukast, and Isavuconazonium for ROS1 mutants (>-8.8 kcal/mol) were found as putative inhibitors. Furthermore, classical molecular dynamics simulation and endpoint binding energy calculation support the considerable stability of the selected docked complexes aided by substantial hydrogen bonding and hydrophobic interactions in comparison to the respective control complexes. Conclusively, the repositioned FDA-approved drugs might be beneficial alone or in synergy to overcome acquired resistance to EGFR and ROS1-positive lung cancers.

• MeSH
• ErbB Receptors * genetics   antagonists & inhibitors   MeSH
• Genomics methods   MeSH
• Protein Kinase Inhibitors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Mutation * MeSH
• Lung Neoplasms * genetics   drug therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   genetics   MeSH
• Drug Repositioning * MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Proto-Oncogene Proteins * genetics   MeSH
• Molecular Docking Simulation MeSH
• Protein-Tyrosine Kinases * genetics   antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: Breast cancer is the most common cancer and the leading cause of cancer death in women. Recent research indicates that human endogenous retroviruses (HERVs) may be linked to carcinogenesis, but the data remain controversial. METHODS: HERVs' expression was evaluated to show the differences between breast cancer and control samples, and their associations with clinicopathological parameters. Gene expression of 12 HERVs, i.e., ERVE-4, ERVW-1, ERVFRD-1, ERVV-1, ERV3-1, ERVH48-1, ERVMER34-1, ERVK-7, ERVK13-1, ERVK11-1, ERVK3-1, and HCP5, was analyzed by qPCR and/or TCGA datasets for breast cancer. RESULTS: ERV3-1, ERVFRD-1, ERVH48-1, and ERVW-1 provided data to support their tumor suppressor roles in breast cancer. ERV3-1 evinced the best performing diagnostic data based on qPCR, i.e. , AUC: 0.819 (p < 0.0001), sensitivity of 72.41%, and specificity of 89.66%. Lower levels of ERV3-1 were noted in advanced stage and higher grades, and significant negative association was found in relation to Ki-67 levels. Oncogenic roles may be inferred for ERVK13-1, ERVV-1, and ERVMER34-1. Data for ERVK-7, ERVE-4, ERVK11-1, and HCP5 remain inconclusive. CONCLUSION: Differential HERV expression may be applicable to evaluate novel biomarkers for breast cancer. However, more research is needed to reveal their real clinical impact, the biological roles, and regulatory mechanisms in breast carcinogenesis.

• MeSH
• Adult MeSH
• Endogenous Retroviruses * genetics   MeSH
• Carcinogenesis * genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Breast Neoplasms * virology   pathology   genetics   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Changes in DNA methylation are common events in the pathogenesis of acute myeloid leukemia (AML) and have been repeatedly reported as associated with prognosis. However, studies integrating these numerous and potentially prognostically relevant DNA methylation changes are lacking. Therefore, we aimed for an overall evaluation of these epigenetic aberrations to provide a comprehensive NGS-based approach of DNA methylation assessment for AML prognostication. RESULTS: We designed a sequencing panel targeting 239 regions (approx. 573 kb of total size) described in the literature as having a prognostic impact or being associated with AML pathogenesis. Diagnostic whole-blood DNA samples of adult AML patients divided into a training (n = 128) and a testing cohort (n = 50) were examined. The libraries were prepared using SeqCap Epi Enrichments System (Roche) and sequenced on MiSeq instrument (Illumina). Altogether, 1935 CpGs affecting the survival (p < 0.05) were revealed in the training cohort. A summarizing value MethScore was then calculated from these significant CpGs. Patients with lower MethScore had markedly longer overall survival (OS) and event-free survival (EFS) than those with higher MethScore (p < 0.001). The predictive ability of MethScore was verified on the independent testing cohort for OS (p = 0.01). Moreover, the proof-of-principle validation was performed using the TCGA dataset. CONCLUSIONS: We showed that comprehensive NGS-based approach of DNA methylation assessment revealed a robust epigenetic signature relevant to AML outcome. We called this signature MethScore and showed it might serve as a strong prognostic marker able to refine survival probability of AML patients.

• MeSH
• Leukemia, Myeloid, Acute * diagnosis   genetics   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Epigenomics MeSH
• Humans MeSH
• DNA Methylation * MeSH
• Prognosis MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Non-small cell lung carcinoma (NSCLC) represents the majority of lung cancer cases, comprising approximately 85 % of the total. The five-year survival rate for NSCLC patients remains discouragingly low. Recently, immunotherapy has emerged as a promising approach. Nevertheless, only a minority of patients experience considerable benefits from these treatments. This highlights the critical need for effective biomarkers that can predict both patient prognosis and response to immunotherapy. CD8+ T cells play a crucial role in cancer immunotherapy. Their presence within tumours is generally indicative of a favourable prognosis and increased efficacy of immunotherapy. This study was undertaken to identify and authenticate a novel biomarker signature based on CD8+ T-cell marker genes, to prognosticate therapeutic responses in individuals afflicted with NSCLC. This in-depth study was based on a total of 1,200 samples, which included four NSCLC specimens analysed through single-cell RNA sequencing (scRNA-seq), 1,000 NSCLC samples obtained from The Cancer Genome Atlas (TCGA) and 196 NSCLC specimens collected from the GSE37745 cohort. In patients with NSCLC, those presenting a favourable risk profile demonstrated notable elevations in specific immune cells while concurrently exhibiting reductions in other types. CD8+ T cells, with their established role in inducing apoptosis in cancer cells, have emerged as crucial predictors and modulators of treatment strategies for NSCLC patients. The combination of single-cell and bulk RNA sequencing has produced a biomarker signature, emphasizing the CD8+ T cells' crucial role in NSCLC prognosis and treatment.

• MeSH
• CD8-Positive T-Lymphocytes * immunology   MeSH
• Immunotherapy * methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Lung Neoplasms * immunology   therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * immunology   therapy   MeSH
• Prognosis MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Carcinoma with apocrine differentiation (AC) is a subtype of breast carcinoma with apocrine features in >90% of the tumor. Molecular studies demonstrate AC has high expression of androgen receptor (AR) mRNA. Pure AC lack estrogen receptor (ER), progesterone receptor (PR), and express AR, with variable human epidermal growth factor 2 (HER2) status. Currently, in triple negative AC, no targetable therapies or specific diagnostic markers exist. MATERIALS AND METHODS: α-Methylacyl CoA racemase (AMACR) expression was investigated as a marker of apocrine differentiation using a single-plex immunoperoxidase stain, and a novel AMACR/p63 dual stain in a subset of cases, across 1) benign apocrine lesions (apocrine metaplasia, adenosis) 2) apocrine DCIS (ADCIS), 3) AC/ invasive ductal carcinoma (IDC) with apocrine features, 4) non-apocrine triple negative breast cancer (TNBC) and 5) IDC, no special type. A sub-set of cases were evaluated by tissue microarray. RESULTS: AMACR expression was increased in both AC and ADCIS, with minimal expression in benign breast tissue, TNBC and IDC, NST cases. In invasive cases, those with positive AMACR (>5% positivity) were significantly associated with higher histologic grade (P = .006), initial N stage (chi squared 0.044), and lack of ER or PR expression (both P < .001), with no correlation with overall survival. Analysis of TCGA breast cancer datasets revealed AMACR expression was significantly higher in molecularly defined apocrine carcinomas relative to basal and luminal subtypes. Moreover, high AMACR expression predicted worse relapse-free and distant-metastasis free survival, among both ER-/PR-/Her2- and ER-/PR-/Her2+ breast cancer cohorts (log-rank P = .081 and .00011, respectively). CONCLUSION: AMACR represents a promising diagnostic and prognostic marker in apocrine breast lesions. Further study is needed to determine the biologic and clinical significance of this protein in AC.

• MeSH
• Humans MeSH
• Neoplasm Recurrence, Local MeSH
• Lymphatic Metastasis MeSH
• Biomarkers, Tumor metabolism   MeSH
• Breast Neoplasms * metabolism   MeSH
• Racemases and Epimerases MeSH
• Receptor, ErbB-2 metabolism   MeSH
• Receptors, Estrogen metabolism   MeSH
• Receptors, Progesterone metabolism   MeSH
• Triple Negative Breast Neoplasms * diagnosis   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

PURPOSE: To understand prognostic immune cell infiltration signatures in neuroendocrine neoplasms (NENs), particularly pheochromocytoma and paraganglioma (PCPG), we analyzed tumor transcriptomic data from The Cancer Genome Atlas (TCGA) and other published tumor transcriptomic data of NENs. METHODS: We used CIBERSORT to infer immune cell infiltrations from bulk tumor transcriptomic data from PCPGs, in comparison to gastroenteropancreatic neuroendocrine tumors (GEPNETs) and small cell lung carcinomas (SCLCs). PCPG immune signature was validated with NanoString immune panel in an independent cohort. Unsupervised clustering of the immune infiltration scores from CIBERSORT was used to find immune clusters. A prognostic immune score model for PCPGs and the other NENs were calculated as a linear combination of the estimated infiltration of activated CD8+/CD4+ T cells, activated NK cells, and M0 and M2 macrophages. RESULTS: In PCPGs, we found five dominant immune clusters, associated with M2 macrophages, monocytes, activated NK cells, M0 macrophages and regulatory T cells, and CD8+/CD4+ T cells respectively. Non-metastatic tumors were associated with activated NK cells and metastatic tumors were associated with M0 macrophages and regulatory T cells. In GEPNETs and SCLCs, M0 macrophages and regulatory T cells were associated with unfavorable outcomes and features, such as metastasis and high-grade tumors. The prognostic immune score model for PCPGs and the NENs could predict non-aggressive and non-metastatic diseases. In PCPGs, the immune score was also an independent predictor of metastasis-free survival in a multivariate Cox regression analysis. CONCLUSION: The transcriptomic immune signature in PCPG correlates with clinical features like metastasis and prognosis.

• MeSH
• Pheochromocytoma * genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Adrenal Gland Neoplasms * genetics   MeSH
• Neuroendocrine Tumors * genetics   MeSH
• Paraganglioma * genetics   MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH