DNA repair defects and implications for immunotherapy

Bever, Katherine M.; Le, Dung T.

doi:10.1172/jci122010

Cited by 67 publications

(56 citation statements)

References 90 publications

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“…A novel promising aspect of the pharmacology of platinum compounds concerns the drug development side, particularly the emerging interest towards novel Pt pro-drugs with immune-modulating effects [56]. Although encouraging results regarding the immunostimulatory properties of Pt drugs are shown in clinical studies [53,57], focused experimental efforts will be necessary to determine the specific contribution of each drug in terms of immune-stimulatory ability when combinations of chemotherapeutic agents are used. The molecular characterization of clinical tumors is already useful to optimize treatment and further improvement may be achieved.…”

Section: Resultsmentioning

confidence: 99%

“…The molecular characterization of clinical tumors is already useful to optimize treatment and further improvement may be achieved. Indeed, tumors characterized by DNA MMR defects and MSI (including cisplatin-resistant tumors) might be more immunogenic than others and thereby more responsive to immune checkpoint inhibitors [31,57]. A better definition of the molecular mechanisms underlying the effects of Pt drugs on the immune system may also be helpful in understanding the side effects of these cytotoxic com-pounds because a patho-physiological role for specific populations of immune cells has been described [58].…”

Section: Resultsmentioning

confidence: 99%

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Novel aspects of the preclinical pharmacology of platinum compounds

2018

J. Mol. Clin. Med.

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Platinum compounds are widely used antitumor agents known to interfere with DNA function by forming DNA crosslinks and DNA-protein crosslinks. Because of their electrophilicity, platinum compounds can interact with nucleophilic residues of all macromolecules. Consequently, this cross-linking inhibits DNA replication in cancer cells. Immunogenic and immunomodulating effects have been ascribed to platinum drugs, with differences and similarities among cisplatin, carboplatin and oxaliplatin. On the one hand, cisplatin is generally unable to induce immunogenic cell death; on the other hand, oxaliplatin appears to be a good inducer, thanks to its capability to efficiently trigger calreticulin exposure to the tumor cell plasma membrane. Conversely, cisplatin, carboplatin and oxaliplatin can relieve immunosuppressive networks e.g., by decreasing PDL-1 and PDL-2 in dendritic and tumor cells. Such drugs are also capable of modulating MHC molecules via IFN-β production and T-cell mediated lysis. The concentrations appear to be key in determining the immunomodulatory properties of these cytotoxic agents, with low in vivo doses usually playing stimulatory effects. As predicted from preclinical models, supportive results have emerged from clinical studies, particularly those based on chemotherapeutic regimens of platinum compounds combined with immunotherapeutics. Future therapeutic interventions are expected to benefit from a better definition of the molecular effects of platinum compounds on the immune system.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Novel aspects of the preclinical pharmacology of platinum compounds

2018

J. Mol. Clin. Med.

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“…Research proved that when DNA repair fails, this damage can lead to carcinogenesis and tumor genomic instability. In this pathway, biological targets involved in immunotherapy can be found [36]. Bile Acid Metabolism has been found to be related to Signaling in Cholestasis, Inflammation, and Cancer [37].…”

Section: Discussionmentioning

confidence: 99%

Nine glycolysis-related gene signature predicting the survival of patients with endometrial adenocarcinoma

Liu

Gao

et al. 2020

Cancer Cell Int

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Background: Endometrial cancer is the fourth most common cancer in women. The death rate for endometrial cancer has increased. Glycolysis of cellular respiration is a complex reaction and is the first step in most carbohydrate catabolism, which was proved to participate in tumors. Methods: We analyzed the sample data of over 500 patients from TCGA database. The bioinformatic analysis included GSEA, cox and lasso regression analysis to select prognostic genes, as well as construction of a prognostic model and a nomogram for OS evaluation. The immunohistochemistry staining, survival analysis and expression level validation were also performed. Maftools package was for mutation analysis. GSEA identified Glycolysis was the most related pathway to EC. qRT-PCR verified the expression level of hub gene in clinical samples. Results: According to the prognostic model using the train set, 9 glycolysis-related genes including B3GALT6, PAM, LCT, GMPPB, GLCE, DCN, CAPN5, GYS2 and FBP2 were identified as prognosis-related genes. Based on nine gene signature, the EC patients could be classified into high and low risk subgroups, and patients with high risk score showed shorter survival time. Time-dependent ROC analysis and Cox regression suggested that the risk score predicted EC prognosis accurately and independently. Analysis of test and train sets yielded consistent results A nomogram which incorporated the 9-mRNA signature and clinical features was also built for prognostic prediction. Immunohistochemistry staining and TCGA validation showed that expression levels of these genes do differ between EC and normal tissue samples. GSEA revealed that the samples of the low-risk group were mainly concentrated on Bile Acid Metabolism. Patients in the low-risk group displayed obvious mutation signatures compared with those in the high-risk group. The expression levels of B3GALT6, DCN, FBP2 and GYS2 are lower in tumor samples and higher in normal tissue samples. The expression of CAPN5 and LCT in clinical sample tissues is just the opposite. Conclusion: This study found that the Glycolysis pathway is associated with EC and screened for hub genes on the Glycolysis pathway, which may serve as new target for the treatment of EC.

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“…A complex DNA repair machinery has evolved to protect genomic integrity in the face of a myriad of DNA damage sources. As DNA repair failure can lead to carcinogenesis and tumor genomic instability, which is considered as portend particular vulnerabilities of the cancer that can be exploited therapeutically (19).…”

Section: Discussionmentioning

confidence: 99%

NEB mutation is associated with high mutational burden and worse colorectal-cancer survival

Yuan

Yan

et al. 2020

Preprint

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Background: Nebulin (NEB) as a protein-coding gene have been well demonstrated its vital roles in skeletal muscles but no study for association between NEB mutation and cancer.Methods: Here, we systematically analyzed mutation spectrum of colorectal cancer (CRC) samples and associations between NEB somatic mutation and CRC patients' tumor mutation burden (TMB) and prognosis by using TCGA-COAD project mutation dataset.Results: Mutational signatures detected from CRC samples indicated pivotal roles of defective DNA damage repair process and polymerase activity in CRC initiation. NEB somatic mutation was found in about 16% CRC patients. Besides, NEB mutation was identified as an independent factor for high CRC TMB and inferior prognosis. Significantly mutated gene (SMG) analysis identified several genes including RNF43, SETD1B, MBD6 and so on, whose mutation states were profoundly influenced by NEB mutation and might be tumor driver genes in CRC initiation and progression.Conclusions: In conclusion, NEB might be a novel CRC-related genes that could affect patients' prognosis by perturbing genome instability.

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DNA repair defects and implications for immunotherapy

Cited by 67 publications

References 90 publications

Novel aspects of the preclinical pharmacology of platinum compounds

Novel aspects of the preclinical pharmacology of platinum compounds

Nine glycolysis-related gene signature predicting the survival of patients with endometrial adenocarcinoma

NEB mutation is associated with high mutational burden and worse colorectal-cancer survival

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