scholarly journals 927 Wilms tumor reveals DNA repair gene hyper-expression is linked to lack of immune infiltration

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A972-A972
Author(s):  
Emily Higgs ◽  
Riyue Bao ◽  
Ken Hatogai ◽  
Thomas Gajewski
Keyword(s):  
Dna Repair ◽  
T Cell ◽  
Tumor Cell ◽  
Wilms Tumor ◽  
Dna Repair Genes ◽  
Cell Numbers ◽  
Pediatric Cancers ◽  
Tumor Immunogenicity ◽  
Tumor Types ◽  
Repair Genes

BackgroundA T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration is critical for expanding immunotherapy efficacy in the clinic. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade.MethodsRNAseq and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from TCGA. Using an 18-gene tumor inflammation signature (TIS) representing activated CD8+ T cells, we identified genes significantly anti-correlated with the signature. Immunofluorescence was performed on metastatic melanoma samples for CD8, MSH2, and the tumor cell marker SOX10, and analyzed for relationship to anti-PD-1 efficacy.ResultsAmong the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. Wilms tumors demonstrated significantly lower T cell inflammation signatures than matched normal kidney samples, other pediatric tumor samples, and adult kidney tumor samples. Pathway analysis identified multiple types of DNA repair were upregulated in Wilms tumor and a score generated from the top 50 DNA repair genes strongly anti-correlated with TIS. This striking negative association was also observed in most adult tumor types. The anti-correlation was found to be independent of tumor mutation burden, suggesting that high expression of DNA repair pathway machinery may restrict tumor immunogenicity by mechanisms beyond prevention neoantigen accumulation. MSH2 was one of the top DNA repair genes identified from the Wilms tumor analysis and was confirmed to have a strong anti-correlation with TIS in melanoma samples from TCGA. Immunofluorescence from an independent cohort of metastatic melanoma patients revealed a significant negative correlation between CD8+ T cell numbers and MSH2+ SOX10+ tumor cell numbers. Additionally, non-responders to anti-PD-1 immunotherapy had significantly higher numbers of MSH2+ SOX10+ tumor cells than responders.ConclusionsIncreased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor, and this was also observed in the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. Strategies targeting DNA repair pathways could be considered as new therapeutic interventions to transform non-T cell-inflamed tumors into immune-responsive tumors.Ethics ApprovalThe study obtained ethics approval under IRB protocol 15-0837.

Identification of the signature genes and network of Reactive Oxygen Species (ROS) related genes and DNA repair genes in Lung Adenocarcinoma (LUAD)

2021 ◽  
Author(s):  
Ye Zhao ◽  
Hai-Ming Feng ◽  
Xiao-Ping Wei ◽  
Wei-Jian Yan ◽  
Bin Li ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Repair ◽  
Tumor Cell ◽  
Lung Adenocarcinoma ◽  
Tumor Cells ◽  
Patient Survival ◽  
Reactive Oxygen ◽  
Dna Repair Genes ◽  
Oxygen Species ◽  
Repair Genes

Abstract Reactive Oxygen Species (ROS) are present in high amount in patients with tumors, and these ROS can kill and destroy tumor cells. Thus, tumor cells upregulate ROS-related genes to protect themselves and reduce their destruction. Cancer cells already damaged by ROS can be repaired by expressing DNA repair genes consequently promoting their proliferation. In this work, lung adenocarcinoma (LUAD) transcriptome data in the TCGA database was analyzed and samples were clustered into 5 ROS-related categories and 6 DNA repair categories. Survival analysis revealed a significant difference in patient survival between the two classification methods. In addition, the samples corresponding to the two categories overlap, thus, the gene expression profile of the same sample with different categories and survival prognosis was further explored, and the connection between ROS-related genes and DNA repair genes was investigated. The interactive sample recombination classification was used, revealing that the patient's prognosis was worse when the ROS-related genes and DNA repair genes were expressed at the same time. The further research on the potential regulatory network of the two categories of genes and the correlation analysis revealed that ROS-related genes and DNA repair genes have a mutual regulatory relationship. The ROS-related genes NQO1, TXNRD1, and PRDX4 could establish links with other DNA repair genes through the DNA repair gene NEIL3, thereby increasing the growth of tumor cells and balancing the level of ROS, leading to tumor cell death and constant damage to the tumor cell repair system, thus prolonging patient survival. Thus, targeting ROS-related genes and DNA repair genes might be a promising strategy in the treatment of LUAD. Finally, a survival prognostic model of ROS-related genes and DNA repair genes was established (TERT, PRKDC, PTTG1, SMUG1, TXNRD1, CAT, H2AFX and PFKP), the risk score might be used as an independent prognostic factor in LUAD patients.

scholarly journals Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma

Oncotarget ◽  
2017 ◽  
Vol 9 (8) ◽  
pp. 7949-7960 ◽  
Author(s):  
Young Kwang Chae ◽  
Jonathan F. Anker ◽  
Preeti Bais ◽  
Sandeep Namburi ◽  
Francis J. Giles ◽  
...  
Keyword(s):  
Dna Repair ◽  
T Cell ◽  
Lung Adenocarcinoma ◽  
Cell Infiltration ◽  
Dna Repair Genes ◽  
T Cell Infiltration ◽  
Activated T Cell ◽  
Repair Genes

scholarly journals Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Isabele F. Moretti ◽  
Antonio M. Lerario ◽  
Marina Trombetta-Lima ◽  
Paula R. Sola ◽  
Roseli da Silva Soares ◽  
...  
Keyword(s):  
Dna Repair ◽  
Tumor Cell ◽  
Cell Fate ◽  
Nuclear Translocation ◽  
Late Phase ◽  
Combined Treatment ◽  
Dna Repair Genes ◽  
Primary Malignancy ◽  
Pathway Activation ◽  
Repair Genes

AbstractGlioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients.

Associations of DNA Repair Gene Polymorphisms in XRCC1 and ERCC2 with Clinical Outcome in ECOG Trial E9486.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1475-1475
Author(s):  
Brian Van Ness ◽  
Emily Blood ◽  
Philip Greipp ◽  
Neil Kay ◽  
Vincent Rajkumar ◽  
...  
Keyword(s):  
Dna Repair ◽  
T Cell ◽  
Clinical Outcome ◽  
Genetic Polymorphisms ◽  
Median Survival ◽  
Dna Repair Genes ◽  
Cell Counts ◽  
Dna Repair Gene ◽  
The Impact ◽  
Repair Genes

Abstract Although multiple myeloma is clinically defined as the accumulation of clonal, malignant plasma cells in the bone marrow, the disease shows significant heterogeneity with regard to morphology, progression and therapeutic response. Our hypothesis is that this heterogeneity likely is due, in part, to germline genetic polymorphisms that contribute significantly to an individual’s disease course and response. In particular, individuals deficient in the repair of DNA damage are not only at high risk for developing cancer, but also could show DNA repair dependent responses associated with DNA damaging therapeutic agents. In this study we examined the association of functional genetic polymorphisms in the DNA repair genes, XRCC1 (SNP positions 280, 399) and ERCC2 (SNP positions 312, 751), with toxicities and clinical outcomes in the ECOG, 3 arm chemotherapeutic trial, E9486 [A-VBMCP, B-VBMCP+Cylophosphamide, C- VBMCP+interferon]. DNA from 359 patients was genotyped and examined for association with response, toxicities, blood counts, bone pathology, and survival parameters. Notably, in the interferon arm of the trial significant associations were observed in progression free survival and polymorphisms of XRCC399 (AA median survival 51 months versus AG/GG median survival of 33 months; p=,008), ERCC751 (AA/AC median survival 33 months versus CC median survival of 48 months; p=.05), and ERCC312 (AA median survival 49 months versus AG/GG median survival of 34 months; p=.02). Hazard ratios ranged form 1.7 to 2.05 for survival differences associated with DNA repair genes in this arm. Interestingly, T cell counts are known to be impacted by interferon; and DNA repair polymorphisms in this arm were also associated with CD8+ T cell counts. While this represents a single arm of one clinical trial, it is intriguing to consider the impact of genetic polymorphisms on DNA repair in light of chemotherapeutic agents that may affect cells of the immune system. Previous studies from the ECOG Myeloma Committee of the E9486 trial show highly significant associations of survival and immune status in myeloma patients. Our results suggest genetic polymorphisms in DNA repair genes may influence clinical outcome in certain therapeutic regimens. Genetic polymorphisms in these DNA repair genes are currently being completed in 800 patients of the SW9321 SWOG/ECOG intergroup trial and additional association studies will be included in the presentation.

Truncating variants in DNA-repair genes and their effect on AAO of hereditary breast cancer

2018 ◽  
Author(s):  
I Sepahi ◽  
U Faust ◽  
M Sturm ◽  
K Bosse ◽  
M Kehrer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Hereditary Breast Cancer ◽  
Dna Repair Genes ◽  
Repair Genes

scholarly journals Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 924
Author(s):  
Laurence Blanchard ◽  
Arjan de Groot
Keyword(s):  
Dna Repair ◽  
Deinococcus Radiodurans ◽  
Dna Repair Genes ◽  
Lesion Bypass ◽  
Radiation Resistant ◽  
Radiation Induced ◽  
Induced Mutagenesis ◽  
High Doses ◽  
Translesion Polymerases ◽  
Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

2014 ◽  
Vol 41 (3) ◽  
pp. 458-465 ◽  
Author(s):  
Gustavo Martelli Palomino ◽  
Carmen L. Bassi ◽  
Isabela J. Wastowski ◽  
Danilo J. Xavier ◽  
Yara M. Lucisano-Valim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Systemic Sclerosis ◽  
Blood Cells ◽  
Gene Polymorphisms ◽  
Peripheral Blood Cells ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

scholarly journals Emergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy

2016 ◽  
Vol 9 (1) ◽  
Author(s):  
Takashi Matono ◽  
Kayoko Hayakawa ◽  
Risen Hirai ◽  
Akira Tanimura ◽  
Kei Yamamoto ◽  
...  
Keyword(s):  
Dna Repair ◽  
Enterococcus Faecium ◽  
High Dose ◽  
Dna Repair Genes ◽  
Repair Genes ◽  
Faecium Strain
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