Carboplatin-resistance-related DNA damage repair prognostic gene signature and its association with immune infiltration in breast cancer
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ABSTRACT:
PROVIDER: PRJNA1181516 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31204681_1.fastq.gz | Fastqsanger.gz | |||
| SRR31204681_2.fastq.gz | Fastqsanger.gz | |||
| SRR31204682_1.fastq.gz | Fastqsanger.gz | |||
| SRR31204682_2.fastq.gz | Fastqsanger.gz | |||
| SRR31204683_1.fastq.gz | Fastqsanger.gz |
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Project description:Breast cancer is among the most prevalent malignant tumors globally, with carboplatin serving as a standard treatment option. However, resistance often compromises its efficacy. DNA damage repair (DDR) pathways are crucial in determining responses to treatment and are also associated with immune infiltration. This study aimed to identify the DDR genes involved in carboplatin resistance and to elucidate their effects on prognosis, immune infiltration, and drug sensitivity in breast cancer patients. We constructed the 3D-culture model of the MDA-MB-231 cell line, both resistant and sensitive to carboplatin, and identified a set of DDR genes. By integrating data from a public database, we established a prognostic signature comprising thirteen DDR genes. Our analysis indicated that this model is associated with immune infiltration patterns in breast cancer patients, particularly concerning CD8+ T cells and NK cells. Additionally, it demonstrated a significant correlation with sensitivity to other DDR-related drugs, suggesting its potential as a biomarker for treatment efficacy. Compared to the control group, TONSL-knockdown cell lines exhibited a diminished response to DNA-damaging agents, marked by a notable increase in DNA damage levels and enhanced drug sensitivity. Furthermore, single-cell analysis revealed elevated TONSL expression in dendritic and epithelial cells, particularly in triple-negative breast cancers.
2025-02-19 | GSE280942 | GEO
Project description:IntroductionBreast cancer is among the most prevalent malignant tumors globally, with carboplatin serving as a standard treatment option. However, resistance often compromises its efficacy. DNA damage repair (DDR) pathways are crucial in determining responses to treatment and are also associated with immune infiltration. This study aimed to identify the DDR genes involved in carboplatin resistance and to elucidate their effects on prognosis, immune infiltration, and drug sensitivity in breast cancer patients.MethodsA 3D-culture model resistant to carboplatin was constructed and sequenced. Co-expressed DDR genes were analyzed to develop a predictive model. Immune infiltration analysis tools were employed to assess the immune microenvironment of patients with varying expression levels of these risk genes. Additionally, drug sensitivity predictions were made to evaluate the efficacy of other DNA damage-related drugs across different risk groups. Molecular assays were performed to investigate the role of the key gene TONSL in breast cancer.ResultsBy integrating data from public database, we established a prognostic signature comprising thirteen DDR genes. Our analysis indicated that this model is associated with immune infiltration patterns in breast cancer patients, particularly concerning CD8+ T cells and NK cells. Additionally, it demonstrated a significant correlation with sensitivity to other DDR-related drugs, suggesting its potential as a biomarker for treatment efficacy. Compared to the control group, TONSL-knockdown cell lines exhibited a diminished response to DNA-damaging agents, marked by a notable increase in DNA damage levels and enhanced drug sensitivity. Furthermore, single-cell analysis revealed elevated TONSL expression in dendritic and epithelial cells, particularly in triple-negative breast cancers.ConclusionsCarboplatin resistance-related DDR genes are associated with prognosis, immune infiltration, and drug sensitivity in breast cancer patients. TONSL may serve as a potential therapeutic target for breast cancer, particularly in triple-negative breast cancer, indicating new treatment strategies for these patients.
| S-EPMC11813922 | biostudies-literature
Project description:Carboplatin mutational signature in HepG2 and MCF10A
| PRJEB30310 | ENA
Project description:ObjectiveGlioma is the most frequent type of malignant cerebral tumors. DNA damage repair genes (DDRGs) play a crucial role in the development of cancer. In this study, we constructed a DDRGs signature and investigated the potential mechanisms involved in this disease.MethodsRNA sequence data, microarray data, and corresponding clinical information of gliomas were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO). Subsequently, we identified candidate genes by differential analysis and Cox regression analysis. The least absolute shrinkage and selection operator Cox regression model was utilized to construct a DDRGs signature using TCGA training dataset. According to this signature, patients with glioma were divided into low- and high-risk groups. The predictive ability of the signature was validated by prognostic analysis, receiver operating characteristic curves, principal component analysis, and stratification analysis in TCGA testing and CGGA verification datasets. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate the immune microenvironment of glioma. Moreover, we conducted GSEA to determine the functions and pathways in the low- and high-risk groups. Finally, a nomogram was constructed by combining the signature and other clinical features.ResultsA total of 1,431 samples of glioma (592 from TCGA, 686 from the CGGA, and 153 from the GEO) and 23 samples of normal brain tissue from the GEO were analyzed in this study. There were 51 prognostic differentially expressed DDRGs. Additionally, five DDRGs (CDK4、HMGB2、WEE1、SMC3 and GADD45G) were selected to construct a DDRGs signature for glioma, stratifying patients into low- and high-risk groups. The survival analysis showed that the DDRGs signature could differentiate the outcome of the low- and high-risk groups, showing that high-risk gliomas were associated with shorter overall survival. The immune microenvironment analysis revealed that more immunosuppressive cells, such as tumor associated macrophages and regulatory T cells, were recruited in the high-risk group. GSEA also showed that high-risk glioma was correlated with the immune and extracellular matrix pathways.ConclusionThe five DDRGs signature and its impact on the infiltration of immunosuppressive cells could precisely predict the prognosis and provide guidance on the treatment of glioma.
| S-EPMC8193723 | biostudies-literature
Project description:We performed a time-course microarray experiment to define the transcriptional response to carboplatin in vitro, and to correlate this with clinical outcome in epithelial ovarian cancer (EOC). RNA was isolated from carboplatin and control-treated 36M2 ovarian cancer cells at several time points, followed by oligonucleotide microarray hybridization. Carboplatin induced changes in gene expression were assessed at the single gene as well as at the pathway level. Clinical validation was performed in publicly available microarray datasets using disease free and overall survival endpoints. Time-course and pathway analyses identified 317 genes and 40 pathways (designated time-course and pathway signatures) deregulated following carboplatin exposure. Both types of signatures were validated in two separate platinum-treated ovarian and NSCLC cell lines using published microarray data. Expression of time-course and pathway signature genes distinguished between patients with unfavorable and favorable survival in two independent ovarian cancer datasets. Among the pathways most highly induced by carboplatin in vitro, the NRF2, NF-kB, and cytokine and inflammatory response pathways were also found to be upregulated prior to chemotherapy exposure in poor prognosis tumors.
2009-01-05 | GSE13525 | GEO
Project description:We performed a time-course microarray experiment to define the transcriptional response to carboplatin in vitro, and to correlate this with clinical outcome in epithelial ovarian cancer (EOC). RNA was isolated from carboplatin and control-treated 36M2 ovarian cancer cells at several time points, followed by oligonucleotide microarray hybridization. Carboplatin induced changes in gene expression were assessed at the single gene as well as at the pathway level. Clinical validation was performed in publicly available microarray datasets using disease free and overall survival endpoints. Time-course and pathway analyses identified 317 genes and 40 pathways (designated time-course and pathway signatures) deregulated following carboplatin exposure. Both types of signatures were validated in two separate platinum-treated ovarian and NSCLC cell lines using published microarray data. Expression of time-course and pathway signature genes distinguished between patients with unfavorable and favorable survival in two independent ovarian cancer datasets. Among the pathways most highly induced by carboplatin in vitro, the NRF2, NF-kB, and cytokine and inflammatory response pathways were also found to be upregulated prior to chemotherapy exposure in poor prognosis tumors. Experiment Overall Design: we treated the 36M2 cell line with carboplatin 100μM or vehicle-control for 24hrs and cells were harvested and processed for RNA isolation at 24, 30 and 36hrs after treatment.
2009-01-14 | E-GEOD-13525 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is the subtype of breast cancer most lacking in efficient treatment options. Although many TNBCs show remarkable responses to carboplatin-based chemotherapy, they often develop resistance over time. With increasing use of carboplatin in clinics, there is a pressing need to understand mechanisms causing carboplatin resistance and identify the vulnerabilities of carboplatin-resistant tumors. We generated carboplatin-resistance models based on the TNBC cell line MDA-MB-468 and patient derived xenograft (PDX) models of TNBCs. By combining the results of mass spectrometry-based proteome profiling and a kinome RNA interference screen, we assessed the molecular changes and vulnerabilities of carboplatin-resistant TNBCs. Using pharmacological inhibition of the identified targets, we validated the dependencies of carboplatin-resistant cells in vitro and in PDX models. We found that carboplatin resistance in TNBC is accompanied by drastic proteome rewiring. Carboplatin-induced metabolism alterations and upregulation of anti-oxidative response keep low levels of DNA damage and support cell replication in the presence of carboplatin. Carboplatin-resistant cells also exhibited longer mitosis due to dysregulation of mitotic checkpoint. Whereas the components of the mitotic checkpoints, AURKA and BUB1, are essential for the viability of carboplatin-resistant cells, the checkpoint kinases CHEK1 and WEE1 are indispensable for survival of carboplatin-treated resistant cells. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Abrogation of the mitotic checkpoint re-sensitizes carboplatin-resistant TNBCs to carboplatin. CHEK1 inhibition represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
2021-07-07 | PXD021726 | Pride
Project description:SK-OV-3 cells under prolonged carboplatin exposition turn into giant cells. This dataset contains the transcriptome of cultured SK-OV-3 cells with and without carboplatin.
2016-04-30 | E-MTAB-3770 | biostudies-arrayexpress
Project description:Background: The mechanism of DNA damage repair plays an important role in many solid tumors represented by cervical cancer. Purpose: The purpose of this study was to explore the effect of DNA damage repair-related genes on immune function of patients with cervical cancer, and to establish and evaluate a prognosis model based on DNA damage repair-related genes. Methods: In the study, we analyzed the genes related to DNA damage and repair, and obtained two subtypes (F1 and F2). We selected two groups of samples for different selection, and studied which pathways were enriched expression. For different subtypes, the immune score was explored to explain immune infiltration. We got the key genes through screening, and established the prognosis model through the key genes. These 11 key genes were correlated with the expression of common Clusters of Differentiation (CD) genes in order to explore the effects of these genes on immunity. Results: Through the Least absolute shrinkage and selection operator (LASSO) method, we screened 11 genes from 232 candidate genes as the key genes for the prognosis score. Through the Kaplan-Meier method, four genes (HAP1, MCM5, RNASEH2A, CETN2) with significant prognostic significance were screened into the final model, forming a Nomogram with C-index of 0.716 (0.649-1.0). Conclusion: In cervical cancer, DNA damage repair related genes and immune cell infection characteristics have certain association, and DNA damage repair related genes and immune cell infection characteristics can effectively predict the prognosis.
| S-EPMC8927729 | biostudies-literature
Project description:Following the re-exposure to lipopolysaccharide (LPS), macrophages exhibit the immunosuppressive state contribute to low production of proinflammatory cytokines and inability to respond the stimuli, a phenomenon is termed “tolerance”. Histone modification has been found in LPS-induced tolerant macrophages. Carboplatin, an antitumor drug, exerts its general effect on inhibition of DNA replication and transcription as well as epigenetic modification. Therefore, we hypothesized that carboplatin can be used to rescue the tolerance in macrophages. We found that carboplatin increases IL-6 but not TNF-α production in LPS-primed cells. The significant inductions were examined in carboplatin-treated tolerant macrophages evaluated by ELISA and qPCR. GSEA analyses revealed that p53 was the significant hallmark in both primed and tolerant RNA-Seq transcripts under carboplatin exposure while E2F ang G2/M were the upmost in negative hallmarks. HP1-α, heterochromatin protein 1, was significantly reduced in carboplatin-treated tolerant macrophages. The significant lower transcript of H3K9me3 methyltransferase, setdb2, was determined whereas kdm4d, demethylase encoding gene was significantly up-regulated in the presence of carboplatin in tolerant macrophages. Based on our data we suggested that carboplatin mediated upregulation of proinflammatory cytokine and rescue tolerance via the H3K9me3 modification. Carboplatin is potentially be a therapeutic drug for tolerance recovery in sepsis patients.
2021-11-10 | GSE179974 | GEO