scholarly journals Pan-cancer analysis of non-oncogene addiction to DNA repair

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luis Bermúdez-Guzmán
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Cell Lines ◽  
The Cancer Genome Atlas ◽  
Molecular Signature ◽  
Systematic Evaluation ◽  
Oncogene Addiction ◽  
Driver Genes ◽  
Using Data ◽  
Pan Cancer

AbstractCancer cells usually depend on the aberrant function of one or few driver genes to initiate and promote their malignancy, an attribute known as oncogene addiction. However, cancer cells might become dependent on the normal cellular functions of certain genes that are not oncogenes but ensure cell survival (non-oncogene addiction). The downregulation or silencing of DNA repair genes and the consequent genetic and epigenetic instability is key to promote malignancy, but the activation of the DNA-damage response (DDR) has been shown to become a type of non-oncogene addiction that critically supports tumour survival. In the present study, a systematic evaluation of DNA repair addiction at the pan-cancer level was performed using data derived from The Cancer Dependency Map and The Cancer Genome Atlas (TCGA). From 241 DDR genes, 59 were identified as commonly essential in cancer cell lines. However, large differences were observed in terms of dependency scores in 423 cell lines and transcriptomic alterations across 18 cancer types. Among these 59 commonly essential genes, 14 genes were exclusively associated with better overall patient survival and 19 with worse overall survival. Notably, a specific molecular signature among the latter, characterized by DDR genes like UBE2T, RFC4, POLQ, BRIP1, and H2AFX showing the weakest dependency scores, but significant upregulation was strongly associated with worse survival. The present study supports the existence and importance of non-oncogenic addiction to DNA repair in cancer and may facilitate the identification of prognostic biomarkers and therapeutic opportunities.

scholarly journals Pan-cancer analysis of non-oncogene addiction to DNA repair

2021 ◽  
Author(s):  
Luis Bermúdez-Guzmán
Keyword(s):  
Overall Survival ◽  
Dna Repair ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
The Cancer Genome Atlas ◽  
Molecular Signature ◽  
Systematic Evaluation ◽  
Oncogene Addiction ◽  
Poor Overall Survival ◽  
Pan Cancer

Abstract Cancer cells usually depend on the aberrant function of one or few driver genes to initiate and promote their malignancy, an attribute known as oncogene addiction. However, cancer cells might become dependent on the normal cellular functions of certain genes that are not oncogenes but ensure cell survival (non-oncogene addiction). The downregulation of DNA repair genes and the consequent genetic and epigenetic instability is key to promote malignancy, but the activation of the DNA-damage response (DDR) has been shown to become a type of non-oncogene addiction that critically supports tumour survival. While we know that different cancer types can become dependent on specific DDR genes for their survival, a systematic evaluation of DNA repair addiction at the pan-cancer level is missing. In the present study, this systematic evaluation was addressed using data derived from The Cancer Dependency Map and The Cancer Genome Atlas (TCGA). Following this approach, 59 DDR genes were identified as commonly essential in cancer cells with 14 genes being exclusively associated with better overall patient survival and 19 with worse overall survival. Notably, a specific molecular signature among the latter, characterized by DDR genes showing the weakest dependency scores, but significant upregulation was strongly associated with worse survival, supporting the presence and relevance of non-oncogenic addiction to DNA repair in cancer. Particularly, UBE2T, RFC4, POLQ, BRIP1, and H2AFX represent the best predictors of poor overall survival, and some might represent promising therapeutic targets, especially under the synthetic lethality approach.

scholarly journals Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiajun He ◽  
Hongjian Ding ◽  
Huaqing Li ◽  
Zhiyu Pan ◽  
Qian Chen
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Mononuclear Cells ◽  
Cancer Cell Lines ◽  
Clinical Practices ◽  
Pan Cancer

While many anti-cancer modalities have shown potent efficacy in clinical practices, cancer prevention, timely detection, and effective treatment are still challenging. As a newly recognized iron-dependent cell death mechanism characterized by excessive generation of lipid peroxidation, ferroptosis is regarded as a potent weapon in clearing cancer cells. The cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) is the core target for ferroptosis regulation, the overexpression of which dictates downregulated sensitivity to ferroptosis in cancer cells. Hence, we elaborated the pan-cancer level bioinformatic study and systematically elucidated the role of intra-tumoral expression of SLC7A11 in the survival of cancer patients and potential immunotherapeutic response. Specifically, 25/27 (92.6%) cancers were featured with upregulated SLC7A11 expression, where SLC7A11 overexpression is a risk factor for worse overall survival in 8 cancers. We also validated SLC7A11 expression in multiple pancreatic cancer cell lines in vitro and found that it was upregulated in most pancreatic cancer cell lines (p < 0.05). Single-cell sequencing method revealed the SLC7A11 was majorly expressed in cancer cells and mononuclear cells. To further explore the function of SLC7A11 in cancer progression, we analyzed the influence on cell proliferation after the knockdown or knockout of SLC7A11 by either CRISPR or RNAi methods. Besides, the association between SLC7A11 and drug resistance was characterized using bioinformatic approaches as well. We also analyzed the association between the expression of SLC7A11 in multi-omics level and the intra-tumoral infiltration of immune cells based on cell annotation algorithms. Moreover, the relationship between SLC7A11 and the expression of MHC, immune stimulators, immune inhibitors as well as the response to immunotherapy was investigated. In addition, the SLC7A11 expression in colon adenocarcinoma, uterine corpus endometrial carcinoma, and stomach adenocarcinoma (STAD) is also positively associated with microsatellite instability and that in head and neck squamous cell carcinoma, STAD, and prostate adenocarcinoma is positively associated with neoantigen level, which further revealed the potential relationship between SLC7A11 and immunotherapeutic response.

scholarly journals Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel R. Principe ◽  
Matthew Narbutis ◽  
Regina Koch ◽  
Ajay Rana
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Parp Inhibition ◽  
Repair Pathway ◽  
Wide Range ◽  
Recombination Pathway ◽  
Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

scholarly journals Unravelling roles of error-prone DNA polymerases in shaping cancer genomes

Oncogene ◽  
2021 ◽  
Author(s):  
Cyrus Vaziri ◽  
Igor B. Rogozin ◽  
Qisheng Gu ◽  
Di Wu ◽  
Tovah A. Day
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Polymerase ◽  
Genome Stability ◽  
Dna Polymerases ◽  
The Cancer Genome Atlas ◽  
Cancer Genomes ◽  
Recent Developments ◽  
Comprehensive Picture

AbstractMutagenesis is a key hallmark and enabling characteristic of cancer cells, yet the diverse underlying mutagenic mechanisms that shape cancer genomes are not understood. This review will consider the emerging challenge of determining how DNA damage response pathways—both tolerance and repair—act upon specific forms of DNA damage to generate mutations characteristic of tumors. DNA polymerases are typically the ultimate mutagenic effectors of DNA repair pathways. Therefore, understanding the contributions of DNA polymerases is critical to develop a more comprehensive picture of mutagenic mechanisms in tumors. Selection of an appropriate DNA polymerase—whether error-free or error-prone—for a particular DNA template is critical to the maintenance of genome stability. We review different modes of DNA polymerase dysregulation including mutation, polymorphism, and over-expression of the polymerases themselves or their associated activators. Based upon recent findings connecting DNA polymerases with specific mechanisms of mutagenesis, we propose that compensation for DNA repair defects by error-prone polymerases may be a general paradigm molding the mutational landscape of cancer cells. Notably, we demonstrate that correlation of error-prone polymerase expression with mutation burden in a subset of patient tumors from The Cancer Genome Atlas can identify mechanistic hypotheses for further testing. We contrast experimental approaches from broad, genome-wide strategies to approaches with a narrower focus on a few hundred base pairs of DNA. In addition, we consider recent developments in computational annotation of patient tumor data to identify patterns of mutagenesis. Finally, we discuss the innovations and future experiments that will develop a more comprehensive portrait of mutagenic mechanisms in human tumors.

scholarly journals Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer

2020 ◽  
Author(s):  
Haitang Yang ◽  
Liang Zhao ◽  
Feng Yao ◽  
Yanyun Gao ◽  
Thomas M. Marti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Gene Networks ◽  
Gene Expression Signature ◽  
The Cancer Genome Atlas ◽  
P Value ◽  
Solid Cancer ◽  
Cancer Drugs ◽  
Pan Cancer

Abstract Background: Ferroptosis is an apoptosis-independent cell death program implicated in various diseases including cancer. Emerging evidence has demonstrated the promise of pharmacological induction of ferroptosis as a novel anti-cancer approach, but the molecular underpinnings of ferroptosis regulation and biomarkers associated with sensitivity to ferroptosis indcuers has been poorly defined. Methods: By implementing integrated pharmacogenomic analysis, we correlated the sensitivity of small-molecule compounds (n=481) against the transcriptomes of solid cancer cell lines (n=659). The potential of a drug compound to modulate ferroptosis was determined by significant (empirical p-value < 0.01) association of drug effectiveness with SLC7A11 expression. To establish generalized gene signatures for ferroptosis sensitivity and resistance, we interrogated drug effects of multiple ferroptosis inducers (n=7) with transcriptomic data of pan-solid cancer cells. Finally, the ferroptosis gene signature was applied to The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) project to identify cancer patients and cells that likely benefit from ferroptosis-based therapeutics. Results: We report, for the first time, the comprehensive identification of cancer drugs with the potential to induce ferroptosis and a generalized gene expression signature predicting ferroptosis response in pan-cancer. Informed by the findings, we reveal an unanticipated role for class I histone deacetylase (HDAC) in regulating ferroptosis and show that targeting HDAC significantly enhances the ferroptosis-promoting effect of Erastin in lung cancer cells. Moreover, our data indicate that small cell lung cancer (SCLC) and isocitrate dehydrogenase ( IDH )-mutant brain tumors are highly primed for ferroptosis, suggesting that relaunching ferroptosis might be an innovative strategy to target these malignancies. Conclusions: Expanding arsenal targeting aberrant ferroptosis and deciphering gene networks dictating ferroptosis sensitivity shed light on ferroptosis regulatory networks and may facilitate biomarker-guided stratification for ferroptosis-based therapy.

scholarly journals ATAC-seq identifies thousands of extrachromosomal circular DNA in cancer and cell lines

2020 ◽  
Vol 6 (20) ◽  
pp. eaba2489 ◽  
Author(s):  
Pankaj Kumar ◽  
Shashi Kiran ◽  
Shekhar Saha ◽  
Zhangli Su ◽  
Teressa Paulsen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Inverse Pcr ◽  
Driver Genes ◽  
Circular Dna ◽  
Cancer Driver ◽  
Genome Wide ◽  
Number Variation ◽  
Circular Dnas ◽  
Tumor Types ◽  
Pan Cancer

Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. More than 18,000 eccDNAs, many carrying known cancer driver genes, are identified in a pan-cancer analysis of ATAC-seq libraries from 23 tumor types. Somatically mosaic eccDNAs are identified by ATAC-seq even before amplification is recognized by genome-wide copy number variation measurements. Thus, ATAC-seq is a sensitive method to detect eccDNA present in a tumor at the pre-amplification stage and can be used to predict resistance to therapy.

scholarly journals A panel of 8-lncRNA predicts prognosis of breast cancer patients and migration of breast cancer cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0249174
Author(s):  
Lili Zhu ◽  
Kang Cui ◽  
Lanling Weng ◽  
Pu Yu ◽  
Yabing Du ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Cox Regression ◽  
Early Stage ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Breast Cancer Patients

Background Breast cancer (BCa) is the most commonly diagnosed cancer and the leading cause of cancer death among females around the world. Recent studies have indicated that long non-coding RNAs (lncRNAs) can serve as an independent biomarker for diagnosis and prognosis in many types of cancer, including pancreatic adenocarcinoma, gastric cancer, liver cancer, and lung cancer. Previous studies have shown that many lncRNAs are associated with the occurrence and development of BCa. However, few studies have combined multiple lncRNAs to predict the prognosis of early-stage BCa patients. Methods Systematic and comprehensive analysis of data from The Cancer Genome Atlas (TCGA) was conducted to identify lncRNA signatures with prognostic value in BCa. Additionally, the relative expression levels of the 8 lncRNA of several BCa cell lines were detected by quantitative real-time PCR (qPCR) and the results were substituted into a risk score formula. Finally, migration assays were used to verify the result from prognostic analysis according to the risk scores among cell lines with different risk scores. Results Our study included 808 BCa patients with complete clinical data. A panel of 8 lncRNAs was identified using Wilcox tests as different between normal and tumor tissue of the BCa patients. This panel was used to analyze the survival of BCa patients. Patients with low risk scores had greater overall survival (OS) than those with high risk scores. Multivariate Cox regression analyses demonstrated that the lncRNA signature was an independent prognostic factor. Gene Set Enrichment Analysis (GSEA) suggested that the lncRNAs might be involved in several molecular signaling pathways implicated in BCa such as the DNA replication pathway, the cell cycle pathway, and the pentose phosphate pathway. Validation experiments in breast cancer cells to test cell migration by using wound-healing assays supported the results of the model. Conclusion Our study demonstrated that a panel of 8 lncRNAs has the potential to be used as an independent prognostic biomarker of BCa.

scholarly journals Pan-Cancer Analysis of Molecular Characteristics and Oncogenic Role of PRMT5 in Human Cancers

2021 ◽  
Author(s):  
He Liu ◽  
Lexi Huang ◽  
Kunpeng Jia ◽  
Xiaohua Pan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
The Cancer Genome Atlas ◽  
Cancer Development ◽  
Nuclear Antigen ◽  
Molecular Characteristics ◽  
Importance Value ◽  
Pan Cancer

Abstract Background Accumulating evidence supports the correlation of protein arginine methyltransferase 5 (PRMT5) and cancers development. However, the expression and prognostic values of PRMT5 in various cancers have not been clarified. Methods Here, based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, we performed a pan-cancer analysis to explore the expression profile , prognostic value landscape, relationship with tumor-infiltrating immune cells, and potential molecular mechanisms of PRMT5 in cancer development. Moreover, CCK8, wound healing and transwell assays, and western blotting analysis were conducted to evaluate how PRMT5 affects the proliferation and migration, and expression of related hallmarks in breast cancer cells. Results We found that PRMT5 was upregulated in most cancers and PRMT5 harbored distinct prognostic values across different cancer types. In addition, PRMT5 expression was negatively correlated with CD8 + T cells in tumors of cervical squamous cell carcinoma and endocervical adenocarcinoma (CSEC) and Skin Cutaneous Melanoma (SKCM), and positively correlated with the cancer-associated fibroblasts in tumors of adrenocortical carcinoma, CESC, cholangio carcinoma, liver hepatocellular carcinoma, pancreatic adenocarcinoma, and SKCM-Primary. Moreover, the enrichment analysis identified that PRMT5 mechanistically regulated cancers development by acting on DNA and RNA metabolism, and stress response related pathways. By further gene silencing experiment, we confirmed tha t PRMT5 knockdown reduced the proliferative and migrative capacities, as well as the expression of PCNA (proliferating cell nuclear antigen), p21 and HMGB1 (high mobility group box 1 protein) in breast cancer cells. Conclusion Collectively, our pan-cancer study highlighted the importance value of PRMT5 in cancer development and prognosis, and pharmacologic targeting at PRMT5 may provide a novel approach for the treatment of cancers.

scholarly journals Radiosensitization of HER2-positive esophageal cancer cells by pyrotinib

2020 ◽  
Vol 40 (2) ◽  
Author(s):  
Xiangyao Lian ◽  
Cuimin Zhu ◽  
Haishan Lin ◽  
Zhengxing Gao ◽  
Guangxin Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Esophageal Cancer ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cell Lines ◽  
Radiation Resistance ◽  
G1 Arrest ◽  
Her2 Positive ◽  
Proliferative Effect ◽  
Esophageal Cancer Cells

Abstract Radiation therapy is a widely used treatment for esophageal cancer. However, radiation resistance might result in a poor prognosis. Overexpression of HER2 has been related to adaptive radiation resistance. Pyrotinib is a HER2 inhibitor that shows an anti-tumor effect in breast cancer. The present study aims to explore the influence of pyrotinib combined with radiotherapy on HER2-positive esophageal cancer cells and explore the underlying mechanism. We screened two cell lines (TE-1 and KYSE30) that highly express HER2 from several human esophageal cancer cell lines. Cells were treated with pyrotinib or/and radiation. Cell proliferation, cell cycle distribution, and cell migration were measured. The protein levels involved in cell cycle and DNA repair were measured by Western blot. Results showed that pyrotinib inhibited HER2 activation and exerted an anti-proliferative effect in TE-1 and KYSE30 cells. Furthermore, it enhanced the anti-proliferative effect of radiation in these two cell lines. These effects might be via inhibiting HER2 phosphorylation, inducing G0/G1 arrest, and reducing EMT and DNA repair. Our results indicated that pyrotinib sensitivitied HER2 positive esophageal cancer cells to radiation treatment through various mechanisms. These findings may provide a new therapeutic strategy for treating HER2 positive esophageal cancer.

scholarly journals INTS8 is a therapeutic target for intrahepatic cholangiocarcinoma via the integration of bioinformatics analysis and experimental validation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi Zhou ◽  
Li Ji ◽  
Xueying Shi ◽  
Dawei Deng ◽  
Fangyue Guo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Therapeutic Target ◽  
Primary Liver Cancer ◽  
Univariate Analysis ◽  
Dna Methyltransferases ◽  
The Cancer Genome Atlas ◽  
Mmr Genes ◽  
Pan Cancer

AbstractIntrahepatic cholangiocarcinoma (CHOL) remains a rare malignancy, ranking as the leading lethal primary liver cancer worldwide. However, the biological functions of integrator complex subunit 8 (INTS8) in CHOL remain unknown. Thus, this research aimed to explore the potential role of INTS8 as a novel diagnostic or therapeutic target in CHOL. Differentially expressed genes (DEGs) in two Gene Expression Omnibus (GEO) datasets were obtained by the “RRA” package in R software. The “maftools” package was used to visualize the CHOL mutation data from The Cancer Genome Atlas (TCGA) database. The expression of INTS8 was detected by performing quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemistry in cell lines and human samples. The association between subtypes of tumour-infiltrating immune cells (TIICs) and INTS8 expression in CHOL was determined by using CIBERSORT tools. We evaluated the correlations between INTS8 expression and mismatch repair (MMR) genes and DNA methyltransferases (DNMTs) in pan-cancer analysis. Finally, the pan-cancer prognostic signature of INTS8 was identified by univariate analysis. We obtained the mutation landscapes of an RRA gene set in CHOL. The expression of INTS8 was upregulated in CHOL cell lines and human CHOL samples. Furthermore, INTS8 expression was closely associated with a distinct landscape of TIICs, MMR genes, and DNMTs in CHOL. In addition, the high INTS8 expression group presented significantly poor outcomes, including overall survival (OS), disease-specific survival (DSS) and disease-free interval (DFI) (p < 0.05) in pan-cancer. INTS8 contributes to the tumorigenesis and progression of CHOL. Our study highlights the significant role of INTS8 in CHOL and pan-cancers, providing a valuable molecular target for cancer research.

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