Prognostic Significance of Nitrative DNA Damage in Infection- and Inflammation-Related Carcinogenesis

2010 ◽  
pp. 341-357
Author(s):  
Yusuke Hiraku ◽  
Shosuke Kawanishi
Keyword(s):  
Dna Damage ◽  
Prognostic Significance ◽  
Infection And Inflammation

scholarly journals High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fahimeh Fattahi ◽  
Leili Saeednejad Zanjani ◽  
Zohreh Habibi Shams ◽  
Jafar Kiani ◽  
Mitra Mehrazma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Prognostic Significance ◽  
Tissue Microarrays ◽  
Survival Outcomes ◽  
Hub Genes ◽  
Kegg Pathways ◽  
Normal Tissues ◽  
Nuclear Expression ◽  
Pathways Analysis

AbstractDNA damage-inducible transcript 4 (DDIT4) is induced in various cellular stress conditions. This study was conducted to investigate expression and prognostic significance of DDIT4 protein as a biomarker in the patients with colorectal cancer (CRC). PPI network and KEGG pathway analysis were applied to identify hub genes among obtained differentially expressed genes in CRC tissues from three GEO Series. In clinical, expression of DDIT4 as one of hub genes in three subcellular locations was evaluated in 198 CRC tissues using immunohistochemistry method on tissue microarrays. The association between DDIT4 expression and clinicopathological features as well as survival outcomes were analyzed. Results of bioinformatics analysis indicated 14 hub genes enriched in significant pathways according to KEGG pathways analysis among which DDIT4 was selected to evaluate CRC tissues. Overexpression of nuclear DDIT4 protein was found in CRC tissues compared to adjacent normal tissues (P = 0.003). Furthermore, higher nuclear expression of DDIT4 was found to be significantly associated with the reduced tumor differentiation and advanced TNM stages (all, P = 0.009). No significant association was observed between survival outcomes and nuclear expression of DDIT4 in CRC cases. Our findings indicated higher nuclear expression of DDIT4 was significantly associated with more aggressive tumor behavior and more advanced stage of disease in the patients with CRC.

Prognostic significance of DNA damage repair (DDR) mutations in patients with urothelial carcinoma (UC) and associations with tumor infiltrating lymphocytes (TILs).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 4538-4538 ◽  
Author(s):  
Russell Bailey McBride ◽  
Vaibhav G. Patel ◽  
Ana Collazo Lorduy ◽  
Mireia Castillo-Martin ◽  
Eugene K. Cha ◽  
...  
Keyword(s):  
Dna Damage ◽  
Urothelial Carcinoma ◽  
Dna Damage Repair ◽  
Prognostic Significance ◽  
Tumor Infiltrating Lymphocytes ◽  
Damage Repair ◽  
Infiltrating Lymphocytes

scholarly journals ATR and p-ATR are emerging prognostic biomarkers and DNA damage response targets in ovarian cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592098285
Author(s):  
Wenlong Feng ◽  
Dylan C. Dean ◽  
Francis J. Hornicek ◽  
Jinglu Wang ◽  
Yanyan Jia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
Ovarian Cancer Cell ◽  
Prognostic Significance ◽  
Ovarian Cancer Cells ◽  
Cancer Tissue ◽  
Damage Response

Background: Although ataxia-telangiectasia and Rad3 related (ATR) has an established role in the DNA damage response of various cancers, its clinical and prognostic significance in ovarian cancer remains largely unknown. The aims of this study were to assess the expression, function, and clinical prognostic relationship of ATR and phospho-ATR ser428 (p-ATR) in ovarian cancer. Methods: We confirmed ATR and p-ATR expression by immunohistochemistry (IHC) in a unique ovarian cancer tissue microarray constructed of paired primary, recurrent, and metastatic tumor tissues from 26 individual patients. ATR-specific small interfering RNA (siRNA) and ATR inhibitor VE-822 were applied to determine the effects of ATR inhibition on ovarian cancer cell proliferation, apoptosis, and DNA damage. ATR expression and the associated proteins of the ATR/Chk1 pathway in ovarian cancer cell lines were evaluated by Western blotting. The clonogenicity was also examined using clonogenic assays. A three dimensional (3D) cell culture model was performed to mimic the in vivo ovarian cancer environment to further validate the effects of ATR inhibition on ovarian cancer cells. Results: We show recurrent ovarian cancer tissues express higher levels of ATR and p-ATR than their patient-matched primary tumor counterparts. Additionally, higher expression of p-ATR correlates with decreased survival in ovarian cancer patients. Treatment of ovarian cancer cells with ATR specific siRNA or ATR inhibitor VE-822 led to significant apoptosis and inhibition of cellular proliferation, with reduced phosphorylation of Chk1 (p-Chk1), Cdc25c (p-Cdc25c), Cdc2 (p-Cdc2), and increased expression of cleaved PARP and γH2AX. Inhibition of ATR also suppressed clonogenicity and spheroid growth of ovarian cancer cells. Conclusion: Our results support the ATR and p-ATR pathway as a prognostic biomarker, and targeting the ATR machinery is an emerging therapeutic approach in the treatment of ovarian cancer.

scholarly journals A DNA-damage immune response assay combined with PET biomarkers predicts response to neo-adjuvant chemotherapy and survival in oesophageal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kieran G. Foley ◽  
Anita Lavery ◽  
Eoin Napier ◽  
David Campbell ◽  
Martin M. Eatock ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Adjuvant Chemotherapy ◽  
Regression Models ◽  
Prognostic Significance ◽  
Pathological Response ◽  
Oesophageal Adenocarcinoma ◽  
Pet Ct ◽  
Neo Adjuvant Chemotherapy ◽  
Additional Value

Abstract18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26–0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26–0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.

scholarly journals Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

2020 ◽  
Author(s):  
Zhongkai Zhang ◽  
Sang Hoon Ha ◽  
Young Jae Moon ◽  
Usama Khamis Hussein ◽  
Yiping Song ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Prognostic Significance ◽  
Repair Pathway ◽  
Anticancer Effects ◽  
Damage Repair ◽  
Anti Cancer ◽  
Resistance To Doxorubicin ◽  
Apoptotic Effects

Abstract Background: SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods: We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results: Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions: This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

The Prognostic Significance Of DUSP3 In DLBCL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3025-3025
Author(s):  
Rachel R. Fang ◽  
Yulian Xu ◽  
Chen-feng Qi ◽  
Herbert Morse ◽  
Jeff Xiwu Zhou
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Control Group ◽  
Damage Response ◽  
Low Levels

Abstract DUSP3 (also called VHR) is a member of the dual-specificity protein phosphatase family which can dephosphorylate target proteins at phosphoserine/threonine and phosphotyrosine residuals. There are evidences that DUSP3 is highly expressed in cervical and prostate cancers, and may exert its function in inhibiting apoptosis. By analyzing publicly available data on diffuse large B-cell lymphoma (DLBCL), we found that the expression levels of DUSP3 mRNA were inversely associated with overall survival (OS) in DLBCL. Patients with low levels of DUSP3 mRNA had significant longer OS than did those with high levels of DUSP3 (P=0.0002) (Figure 1). The association between the levels of DUSP3 mRNA and clinical outcome was confirmed using an independent DLBCL cohort. To decipher the role of DUSP3 in DLBCL, we used lentiviral system to stably express shRNA against DUSP3 in the DLBCL cell line, OCI-Ly01. Reduced expression of DUSP3 was associated with significantly decreased proliferation of cells as compared to the control group (P<0.001) (Figure 2). Because the standard chemotherapy for DLBCL depends largely on induction of DNA damage, we were interested in examining possible effects of DUSP3 on the DNA damage response. We found that the levels of phosphorylated H2A.X, a marker for DNA damage response, were significantly increased in cells with reduced levels of DUSP3 (P<0.01) (Figure 3). This may suggest that low levels of DUSP3 in tumor tissues render cells more vulnerable to therapy-induced DNA damage, leading to increasing efficacy of chemotherapy. More molecular and animal studies are underway to determine if DUSP3 can serve as a prognostic biomarker for DLBCL and to identify the underlying molecular mechanisms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Prevalence of PPM1D Mutations in Therapy-Related AML/MDS Is Due to Context-Specific Clonal Hematopoiesis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 746-746
Author(s):  
Joanne Hsu ◽  
Tajhal Dayaram ◽  
Ayala Tovy ◽  
Etienne De Braekeleer ◽  
Mira Jeong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Peripheral Blood ◽  
Somatic Mutations ◽  
De Novo ◽  
Prognostic Significance ◽  
Specific Treatment ◽  
Chemotherapeutic Agents ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Fitness Advantage

Abstract Clonal hematopoiesis (CH) is a condition in which individual hematopoietic stem cells (HSCs) acquire a fitness advantage and contribute disproportionately to peripheral blood production. Somatic mutations in around 20 genes are recurrently associated with CH, with truncating mutations in PPM1D being among the most common. PPM1D encodes the WIP1 protein (Wildtype p53-Induced Phosphatase 1), which is upregulated by p53 during DNA damage and acts homeostatically to downregulate the DNA damage response (DDR). More recently, PPM1D mutations have been observed in the blood of individuals who had previously been exposed to chemotherapeutic agents for prior malignancies. The effect of PPM1D truncating mutations on hematopoiesis remains unclear, as does the precise mechanism by which PPM1D mutations confer a fitness advantage to hematopoietic stem and progenitor cells in CH. To explore the prevalence and features of PPM1D mutations in a focused subset of patients with prior chemotherapy exposure, we screened for PPM1D mutations in 156 patients with t-AML (n=77) and t-MDS (n=79) by targeted-capture deep sequencing of PPM1D and 295 cancer genes. Truncating mutations in PPM1D were detected in 31/156 cases (20%) with a mean VAF of 0.105 (range 0.02-0.48), making it the second most commonly mutated gene in t-AML/MDS after TP53 (29%). In contrast, PPM1D mutations were detected in only 0.5% of a matched de novo MDS/AML cohort, confirming a specific enrichment in therapy-related cases (Fig 1a). Notably, PPM1D-mutant CH was specifically associated with prior exposure to platinum agents (p=0.004) and etoposide (p=0.021). To investigate the mechanisms behind this clinical association, we created PPM1D truncating mutations in multiple cell lines using CRISPR-Cas9. The truncated WIP1 protein was highly stabilized, leading to a net hyperactive effect on the dephosphorylation of DDR pathway members including phospho-p53 and γH2AX. We next asked whether this translates to chemoresistance, by comparing the sensitivities of PPM1D-mutant and wild-type (WT) cells to various agents. PPM1D mutants were resistant to DNA-damaging agents such as cisplatin, etoposide and doxorubicin, but not to vincristine, a microtubule inhibitor, indicating enhanced survival in specific contexts. We then asked whether this conferred an advantage, by competing PPM1D-mutant and WT cells in vitro with multiple exposures. PPM1D mutants did not have an advantage at baseline or in the context of vincristine, but significantly outcompeted their WT counterparts when exposed to cisplatin, etoposide, and doxorubicin. Annexin V staining revealed that PPM1D mutants exhibit diminished apoptosis with DDR-inducing agents, explaining most of their competitive advantage. Co-treatment with a PPM1D inhibitor reversed this gain and may have clinical implications. To understand the in vivo parameters that impact PPM1D-mutant cell fitness, we next generated a novel Ppm1d truncated knock-in mouse model. Characterization of baseline hematopoiesis in the Ppm1d mutant mouse revealed no appreciable differences in lineage composition or proportion of hematopoietic progenitors. To analyze the factors that impact clonal evolution, we competed Ppm1d-mutant and WT cells in specific proportions in bone marrow transplantation. In the context of stress from transplantation alone, Ppm1d-mutant and WT HSCs remained at the same proportions as the initial transplant. Similarly, serial transplantation did not alter their relative contributions to peripheral blood production. In contrast, competitively transplanted mice treated with cisplatin demonstrated a striking selection for Ppm1d mutants in both the peripheral blood (Fig 1b) and LT-HSCs, suggesting that Ppm1d-mutant clones achieve greater fitness and gain a selective advantage under specific extrinsic stressors. This differs from CH-associated mutations in DNMT3A and TET2, where intrinsic characteristics such as enhanced self-renewal appear sufficient to drive clonal expansion. Broadly, this study highlights the significance of context-specificity underlying CH of different somatic mutations. Furthermore, these findings establish the prognostic significance of CH in the development of t-AML/MDS and demonstrate the importance of understanding specific treatment <-> mutation interactions to inform choices of therapeutic interventions in patients with primary cancers. Disclosures Vassiliou: Celgene: Research Funding; KYMAB: Consultancy, Equity Ownership.

scholarly journals Synergistic role of BAP1 and DNA damage response pathway in uveal melanoma and its prognostic significance

2019 ◽  
Vol 30 ◽  
pp. v803
Author(s):  
J. Jha ◽  
M.K. Singh ◽  
L. Singh ◽  
N. Pushker ◽  
S. Sen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Uveal Melanoma ◽  
Dna Damage Response ◽  
Prognostic Significance ◽  
Damage Response ◽  
Dna Damage Response Pathway

scholarly journals Inhibition of SIRT6 Potentiates the Anti-Tumor Effect of Doxorubicin through Suppression of the DNA Damage Repair Pathway in Osteosarcoma

2020 ◽  
Author(s):  
Zhongkai Zhang ◽  
Sang Hoon Ha ◽  
Young Jae Moon ◽  
Usama Khamis Hussein ◽  
Yiping Song ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Prognostic Significance ◽  
Repair Pathway ◽  
Anticancer Effects ◽  
Damage Repair ◽  
Anti Cancer ◽  
Resistance To Doxorubicin ◽  
Apoptotic Effects

Abstract Background SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

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