scholarly journals APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

Oncotarget ◽  
2017 ◽  
Vol 9 (4) ◽  
pp. 4537-4548 ◽  
Author(s):  
Alexander P. Glaser ◽  
Damiano Fantini ◽  
Yiduo Wang ◽  
Yanni Yu ◽  
Kalen J. Rimar ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Urothelial Carcinoma ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

2017 ◽  
Author(s):  
Alexander P. Glaser ◽  
Damiano Fantini ◽  
Kalen J. Rimar ◽  
Joshua J. Meeks
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Dna Damage ◽  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Dna Damage Response ◽  
Molecular Subtype ◽  
Regulatory Genes ◽  
Enrichment Score ◽  
Damage Response

AbstractBackgroundThe APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.MethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into “APOBEC-high” and “APOBEC-low” tumors based on APOBEC enrichment score. Analysis was performed with R.FindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations inFGFR3andKRAS. APOBEC3AandAPOBEC3Bexpression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.InterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate forAPOBEC3AandAPOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.HighlightsABPOEC enzymes, particularlyAPOBEC3AandAPOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancerTumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations inKRASandFGFR3APOBEC enrichment is associated with upregulation of genes involved in the immune response

scholarly journals DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

2019 ◽  
Vol 21 (1) ◽  
pp. 55 ◽  
Author(s):  
Vassilis L. Souliotis ◽  
Nikolaos I. Vlachogiannis ◽  
Maria Pappa ◽  
Alexandra Argyriou ◽  
Panagiotis A. Ntouros ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Dna Damage ◽  
Autoimmune Diseases ◽  
Dna Damage Response ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Tissue Injury ◽  
Systemic Autoimmune Diseases ◽  
Damage Response

The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

scholarly journals DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma

2017 ◽  
Vol 23 (14) ◽  
pp. 3610-3618 ◽  
Author(s):  
Min Yuen Teo ◽  
Richard M. Bambury ◽  
Emily C. Zabor ◽  
Emmet Jordan ◽  
Hikmat Al-Ahmadie ◽  
...  
Keyword(s):  
Dna Damage ◽  
Urothelial Carcinoma ◽  
Dna Damage Response ◽  
Repair Gene ◽  
Damage Response ◽  
Advanced Urothelial Carcinoma ◽  
Gene Alterations

scholarly journals Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies

2018 ◽  
Vol 10 ◽  
pp. 175883591878665 ◽  
Author(s):  
Anna Minchom ◽  
Caterina Aversa ◽  
Juanita Lopez
Keyword(s):  
Cell Cycle ◽  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Genomic Stability ◽  
Critical Determinant ◽  
Potential Biomarker ◽  
Damage Response

Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit – for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.

Targeting DNA damage response and repair genes to enhance anticancer immunotherapy: rationale and clinical implication

2020 ◽  
Author(s):  
Giuseppe Lamberti ◽  
Elisa Andrini ◽  
Monia Sisi ◽  
Alessandro Di Federico ◽  
Biagio Ricciuti
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Immune Checkpoint ◽  
Therapeutic Strategy ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Antitumor Immune Response ◽  
Endogenous Factors ◽  
Damage Response

DNA damage response and repair ( DDR) genes play a central role in the life of actively replicating cells, cooperating to maintenance of genomic integrity. However, exogenous or endogenous factors, including deficiency in DDR genes, can cause different degrees of DNA damage that profoundly impacts the tumor immunogenicity and enhance antitumor immune response through neoantigen-dependent and neoantigen-independent mechanisms. Inhibition of DDRs is already an effective therapeutic strategy in different cancer types. In addition, because DDR inhibition can also induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses, combining DDR inhibitors with immune checkpoint inhibitors represent an attractive therapeutic strategy to potentially improve the clinical outcomes of patients with metastatic cancer. In this review, we provide an overview of the rational and potential of combining DDR and immune checkpoint inhibition to exploit the enhanced antitumor immune response induced by DNA damage.

scholarly journals The Multifunctional Protein p62 and Its Mechanistic Roles in Cancers

2019 ◽  
Vol 19 (6) ◽  
pp. 468-478 ◽  
Author(s):  
Shunbin Ning ◽  
Ling Wang
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Chronic Inflammation ◽  
Dna Damage Response ◽  
Translational Regulation ◽  
Multifunctional Protein ◽  
Selective Autophagy ◽  
Cellular Processes ◽  
Promising Strategy ◽  
Damage Response

The multifunctional signaling hub p62 is well recognized as a ubiquitin sensor and a selective autophagy receptor. As a ubiquitin sensor, p62 promotes NFκB activation by facilitating TRAF6 ubiquitination and aggregation. As a selective autophagy receptor, p62 sorts ubiquitinated substrates including p62 itself for lysosome-mediated degradation. p62 plays crucial roles in myriad cellular processes including DNA damage response, aging/senescence, infection and immunity, chronic inflammation, and cancerogenesis, dependent on or independent of autophagy. Targeting p62-mediated autophagy may represent a promising strategy for clinical interventions of different cancers. In this review, we summarize the transcriptional and post-translational regulation of p62, and its mechanistic roles in cancers, with the emphasis on its roles in regulation of DNA damage response and its connection to the cGAS-STING-mediated antitumor immune response, which is promising for cancer vaccine design.

scholarly journals Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers

2018 ◽  
Vol 36 (17) ◽  
pp. 1685-1694 ◽  
Author(s):  
Min Yuen Teo ◽  
Kenneth Seier ◽  
Irina Ostrovnaya ◽  
Ashley M. Regazzi ◽  
Brooke E. Kania ◽  
...  
Keyword(s):  
Dna Damage ◽  
Overall Survival ◽  
Urothelial Carcinoma ◽  
Dna Damage Response ◽  
Response Rate ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Long Term Outcome ◽  
Damage Response ◽  
Metastatic Urothelial Carcinoma

Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases. DDR alterations also were associated with longer progression-free and overall survival. Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response.

Sign in / Sign up

Export Citation Format

Share Document