- Publikační typ
- abstrakt z konference MeSH
High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes.
- MeSH
- chemorezistence * genetika MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nádorový supresorový protein p53 * genetika MeSH
- nádory vaječníků * genetika farmakoterapie patologie MeSH
- platina terapeutické užití farmakologie MeSH
- regulace genové exprese u nádorů MeSH
- sekvenování exomu metody MeSH
- senioři MeSH
- serózní cystadenokarcinom * genetika farmakoterapie patologie MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
I přes velice nízké zastoupení boru v zemské kůře nalezly bor i jeho sloučeniny široké uplatnění v praktickém životě i ve vědeckém výzkumu. Článek zmiňuje důležitost tohoto prvku pro rostliny a pro člověka. Podává stručný přehled o vlastnostech boru a jeho sloučenin a jejich technickém využití pro přípravu skel, skelných vláken, vysoce odolných a tvrdých materiálů pro průmyslové využití a pro jadernou technologii. Uvádí také využití borových sloučenin v lékařství a v syntetické chemii.
Despite the very low proportion of boron in the Earth's crust, boron and its compounds have found wide application in practical life and in scientific research. The article presents the importance of this element for plants and for humans. It enumerates the properties of boron and its compounds for the technical use in the preparation of glass, glass fibres, highly resistant and hard materials for industrial applications and for nuclear technology. It also mentions the use of boron compounds in medicine and synthetic chemistry.
BACKGROUND: Colorectal cancer is a highly prevalent and deadly. The most common metastatic site is the liver. We performed a whole exome sequencing analysis of a series of metachronous colorectal cancer liver metastases (mCLM) and matched non-malignant liver tissues to investigate the genomic profile of mCLM and explore associations with the patients' prognosis and therapeutic modalities. METHODS: DNA samples from mCLM and non-malignant liver tissue pairs (n = 41) were sequenced using whole exome target enrichment and their germline and somatic genetic variability, copy number variations, and mutational signatures were assessed for associations with relapse-free (RFS) and overall survival (OS). RESULTS: Our genetic analysis could stratify all patients into existing targeted therapeutic regimens. The most commonly mutated genes in mCLM were TP53, APC, and KRAS together with PIK3CA and several passenger genes like ABCA13, FAT4, PCLO, and UNC80. Patients with somatic alterations in genes from homologous recombination repair, Notch, and Hedgehog pathways had significantly prolonged RFS, while those with altered MYC pathway genes had poor RFS. Additionally, alterations in the JAK-STAT pathway were prognostic of longer OS. Patients bearing somatic variants in VIPR2 had significantly shorter OS and those with alterations in MUC16 prolonged OS. Carriage of the KRAS-12D variant was associated with shortened survival in our and external datasets. On the other hand, tumor mutation burden, mismatch repair deficiency, microsatellite instability, mutational signatures, or copy number variation in mCLM had no prognostic value. CONCLUSIONS: The results encourage further molecular profiling for personalized treatment of colorectal cancer liver metastases discerning metachronous from synchronous scenarios.
- Publikační typ
- časopisecké články MeSH
Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N = 162 in total) with early-stage estrogen-receptor-positive luminal BC-high-coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro-RNA (miRNA) transcriptome microarrays-we describe complex oxysterol-related interaction (correlation) networks, with validation in public datasets (n = 538) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, interconnected through miR-125b-5p, miR-99a-5p, miR-100-5p, miR-143-3p, miR-199b-5p, miR-376a-3p, and miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol-related genes. STARD5 was upregulated in patients with positive lymph node status. High expression of hsa-miR-19b-3p was weakly associated with poor survival. This is the first study of oxysterol-related genes in BC that combines DNA, mRNA, and miRNA multiomics with detailed clinical data. Future studies should provide links between intratumoral oxysterol signaling depicted here, circulating oxysterol levels, and therapy outcomes, enabling eventual clinical exploitation of present findings.
- MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- mikro RNA * genetika metabolismus MeSH
- nádory prsu * patologie MeSH
- oxysteroly * MeSH
- transkriptom genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: Analysis of somatic variant profiles in retrospectively collected pairs of primary tumors and synchronous liver metastases from surgically treated patients with colorectal carcinomas. Mutational profiles were compared between groups of patients stratified by response to chemotherapy and survival. PATIENTS AND METHODS: The study used whole-exome sequencing of tumor sample pairs from 20 patients diagnosed and treated at a single center. The Cancer Genome Atlas COAD-READ data set (n = 380) was used for validation in silico, where possible. RESULTS: The most frequently altered oncodrivers were APC (55% in primaries and 60% in metastases), TP53 (50/45), TRIP11 (30/5), FAT4 (20/25), and KRAS (15/25). Harboring variants with a high or moderate predicted functional effect in KRAS in primary tumors was significantly associated with poor relapse-free survival in both our sample set and the validation data set. We found a number of additional prognostic associations, including mutational load, alterations in individual genes, oncodriver pathways, and single base substitution (SBS) signatures in primary tissues, which were not confirmed by validation. Altered ATM, DNAH11, and MUC5AC, or a higher share of SBS24 signature in metastases seemed to represent poor prognostic factors, but because of a lack of suitable validation data sets, these results must be treated with extreme caution. No gene or profile was significantly associated with response to chemotherapy. CONCLUSION: Taken together, we report subtle differences in exome mutational profiles between paired primary tumors and synchronous liver metastases and a distinct prognostic relevance of KRAS in primary tumors. Although the general scarcity of primary tumor-synchronous metastasis sample pairs with high-quality clinical data makes robust validation difficult, this study provides potentially valuable data for utilization in precision oncology and could serve as a springboard for larger studies.
- MeSH
- individualizovaná medicína MeSH
- kolorektální nádory * farmakoterapie genetika MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- nádory jater * farmakoterapie genetika MeSH
- prognóza MeSH
- protoonkogenní proteiny p21(ras) genetika MeSH
- retrospektivní studie MeSH
- sekvenování exomu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Epithelial ovarian carcinoma (EOC) is known for high mortality due to diagnosis at advanced stages and frequent therapy resistance. Previous findings suggested that the DNA repair system is involved in the therapeutic response of cancer patients and DNA repair genes are promising targets for novel therapies. This study aimed to address complex inter-relations among gene expression levels, methylation profiles, and somatic mutations in DNA repair genes and EOC prognosis and therapy resistance status. We found significant associations of DUT expression with the presence of peritoneal metastases in EOC patients. The high-grade serous EOC subtype was enriched with TP53 mutations compared to other subtypes. Furthermore, somatic mutations in XPC and PRKDC were significantly associated with worse overall survival of EOC patients, and higher FAAP20 expression in platinum-resistant than platinum-sensitive patients was observed. We found higher methylation of RAD50 in platinum-resistant than in platinum-sensitive patients. Somatic mutations in BRCA1 and RAD9A were significantly associated with higher RBBP8 methylation in platinum-sensitive compared to platinum-resistant EOC patients. In conclusion, we discovered associations of several candidate genes from the DNA repair pathway with the prognosis and platinum resistance status of EOC patients, which deserve further validation as potential predictive biomarkers.
- Publikační typ
- časopisecké články MeSH
Taxanes are widely used in the treatment of ovarian carcinomas. One of the main problems with conventional taxanes is the risk of development of multidrug resistance. New-generation synthetic experimental taxoids (Stony Brook Taxanes; SB-T) have shown promising effects against various resistant tumor models. The aim of our study was to compare the in vitro efficacy, intracellular content, and in vivo antitumor effect of clinically used paclitaxel (PTX) and SB-Ts from the previously tested second (SB-T-1214, SB-T-1216) and the newly synthesized third (SB-T-121402, SB-T-121605, and SB-T-121606) generation in PTX resistant ovarian carcinoma cells NCI/ADR-RES. The efficacy of the new SB-Ts was up to 50-times higher compared to PTX in NCI/ADR-RES cells in vitro. SB-T-121605 and SB-T-121606 induced cell cycle arrest in the G2/M phase much more effectively and their intracellular content was 10-15-times higher, when compared to PTX. Incorporation of SB-T-121605 and SB-T-121606 into therapeutic regimens containing PTX were effective in suppressing tumor growth in vivo in NCI/ADR-RES based mice xenografts at small doses (≤3 mg/kg), where their adverse effects were eliminated. In conclusion, new SB-T-121605 and SB-T-121606 analogs are promising candidates for the next phase of preclinical testing of their combination therapy with conventional taxanes in resistant ovarian carcinomas.
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Epithelial ovarian carcinoma (EOC) is highly fatal because of the risk of resistance to therapy and recurrence. We performed whole-exome sequencing of blood and tumor tissue pairs of 50 patients with surgically resected EOC. Compared with sensitive patients, platinum-resistant patients had a significantly higher somatic mutational rate in <i>TP53</i> and lower in several genes from the Hippo pathway. We confirmed the pivotal role of somatic mutations in homologous recombination repair genes in platinum sensitivity and favorable prognosis of EOC patients. Implementing the germline homologous recombination repair profile significantly improved the prediction. In addition, distinct mutational signatures, for example, SBS6, and overall mutational load, somatic mutations in <i>PABPC1</i>, <i>PABPC3</i>, and <i>TFAM</i> co-segregated with the resistance status, high-grade serous carcinoma subtype, or overall survival of patients. We generated germline and somatic genetic landscapes of prognostically different subgroups of EOC patients for further follow-up studies focused on utilizing the observed associations in precision oncology.
- MeSH
- epiteliální ovariální karcinom farmakoterapie genetika MeSH
- individualizovaná medicína MeSH
- lidé MeSH
- nádory vaječníků * farmakoterapie genetika MeSH
- platina * farmakologie terapeutické užití MeSH
- sekvenování exomu MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
