Pan-Cancer Prediction of Immunotherapy Benefit Using DNA Damage Response and Repair Gene Signature: A Model Development and Validation Study

2021 ◽  
Author(s):  
Yiming Zhao ◽  
Xin Du ◽  
Ziwei Zhou ◽  
Si Chen ◽  
Wenkui Fu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Validation Study ◽  
Model Development ◽  
Gene Signature ◽  
Repair Gene ◽  
Cancer Prediction ◽  
Damage Response ◽  
Development And Validation ◽  
Pan Cancer

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

Mutation of the DNA damage gene signature to predict for better outcome in malignant melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21036-e21036
Author(s):  
Mahesh Y. Iddawela ◽  
Arun Azad ◽  
Gail Risbridger
Keyword(s):  
Dna Damage ◽  
Malignant Melanoma ◽  
Dna Damage Response ◽  
Hot Spot ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Parp Inhibition ◽  
Data Repositories ◽  
Public Data ◽  
Damage Response

e21036 Background: DNA damage response is a fundamental cellular pathway with an important role in maintaining genomic integrity. As Malignant Melanoma (MM) is associated with high mutation rates, and we postulated that mm is likely to have abnormal DNA repair pathway aberrations that could have prognostic and/or therapeutic significance. Methods: We conducted an unbiased assessment of genes involved in the DNA damage response through a comprehensive survey of established public data repositories and published literature and abstracts in all cancers. This survey was used to generate a 6-gene DNA Damage Signature (DDS). The DDS was then applied to 287 mm samples in The Cancer Genome Atlas. Results: The DDS was altered in 25% (72/287) of patients with mutations being present in all 6 genes including ATM (6%), TP53BP1 (7%), MDC1 (7%), BRCA1 (5%), PRKDC (8%) and RAD50 (1.4%). The DDS was more commonly altered in mm harboring alterations in BRAF (78%, 112/143), NRAS (89%, 73/82) or NF1 (75%, 5/20) than in triple wild type tumors (60%,19/32). The correlation between alteration in BRAF/NRAS/NF1 and DDS (p = 0.02) reached significance, as did the tendency for DDS and NF1 altered subtype to co-occur (p < 0.05). Importantly, alteration in the DDS was associated with significantly longer disease free (88 vs. 44 months, p = 0.02) and overall survival (152 vs. 66 months, P = 0.02). The mutations in ATM and BRCA1, shown to be targets in other cancers for PARP inhibition were seen in these patients as well as other oncogenic or hot-spot mutations. Conclusions: The improved survival associated with alteration of the DDS implicate DNA damage response signaling as favorably modulating the immune system, and propose a possible role for PARP inhibition as a therapeutic strategy in melanoma.

scholarly journals DNA Damage Response Genes in Osteosarcoma

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Ying Tang ◽  
Yan-xia Liu ◽  
Xiuning Huang ◽  
Peng Li
Keyword(s):  
Dna Damage ◽  
High Risk ◽  
Dna Damage Response ◽  
Risk Score ◽  
Cox Regression ◽  
Excision Repair ◽  
Gene Signature ◽  
Low Risk ◽  
Cox Regression Analysis ◽  
Damage Response

Background. Improving the osteosarcoma (OS) patients’ survival has long been a challenge, even though the disease’s treatment is on the verge of progress. DNA damage response (DDR) has traditionally been associated with carcinogenesis, tumor growth, and genomic instability. No study has used DDR genes as a signature to identify the prognosis of OS. The goal of this work was to find an effective possible DDR gene biomarker for predicting OS prognosis, which may be useful in clinical diagnosis and therapy. Methods. To assess gene methylation, univariate and multivariate cox regression analyses were performed on data from OS patients. The data were retrieved from public databases, including the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and the Gene Expression Omnibus (GEO). Results. The DDR gene signature was chosen, which included seven genes (NHEJ1, RMI2, SWI5, ERCC2, CLK2, POLG, and MLH1). In the TARGET dataset, patients were categorized into two groups: high-risk and low-risk. Patients with a high-risk score revealed a shorter OS rate (hazard ratio (HR): 3.15, 95% confidence interval (CI): 1.38–4.34, P < 0.001 ) in comparison with the patients with a low-risk score in the TARGET as a training group. The validation of the prognostic signature accuracy was carried out in relapse and validation cohorts (TARGET, n = 75; GSE21257, n = 53). The signature was found to be an independent predictive factor for OS in multivariate cox regression analysis, and a nomogram model was developed to predict an individual’s risk of OS. DDR gene signature involved in Fanconi anemia pathway, nonhomologous end−joining pathway, mismatch repair, and nucleotide excision repair pathway. Conclusions. Our study suggests that the identified novel DDR genes could be a powerful prognostic tool for prognosis evaluation and a valuable tool in predicting the risk factors in OS patients.

Primary cilia and the DNA damage response: linking a cellular antenna and nuclear signals

2021 ◽  
Author(s):  
Ciaran G. Morrison
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Developmental Disorders ◽  
Cell Periphery ◽  
Repair Gene ◽  
Control Of Gene Expression ◽  
Damage Response

The maintenance of genome stability involves integrated biochemical activities that detect DNA damage or incomplete replication, delay the cell cycle, and direct DNA repair activities on the affected chromatin. These processes, collectively termed the DNA damage response (DDR), are crucial for cell survival and to avoid disease, particularly cancer. Recent work has highlighted links between the DDR and the primary cilium, an antenna-like, microtubule-based signalling structure that extends from a centriole docked at the cell surface. Ciliary dysfunction gives rise to a range of complex human developmental disorders termed the ciliopathies. Mutations in ciliopathy genes have been shown to impact on several functions that relate to centrosome integrity, DNA damage signalling, responses to problems in DNA replication and the control of gene expression. This review covers recent findings that link cilia and the DDR and explores the various roles played by key genes in these two contexts. It outlines how proteins encoded by ciliary genes impact checkpoint signalling, DNA replication and repair, gene expression and chromatin remodelling. It discusses how these diverse activities may integrate nuclear responses with those that affect a structure of the cell periphery. Additional directions for exploration of the interplay between these pathways are highlighted, with a focus on new ciliary gene candidates that alter genome stability.

scholarly journals Identification of a Ten-Gene Signature of DNA Damage Response Pathways with Prognostic Value in Esophageal Squamous Cell Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Weitao Zhuang ◽  
Xiaosong Ben ◽  
Zihao Zhou ◽  
Yu Ding ◽  
Yong Tang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Squamous Cell ◽  
Cox Regression ◽  
Cell Cancer ◽  
Gene Expression Signature ◽  
Treatment Decision ◽  
Prognostic Indicator ◽  
Gene Signature ◽  
Damage Response

Molecular prognostic signatures are critical for treatment decision-making in esophageal squamous cell cancer (ESCC), but the robustness of these signatures is limited. The aberrant DNA damage response (DDR) pathway may lead to the accumulation of mutations and thus accelerate tumor progression in ESCC. Given this, we applied the LASSO Cox regression to the transcriptomic data of DDR genes, and a prognostic DDR-related gene expression signature (DRGS) consisting of ten genes was constructed, including PARP3, POLB, XRCC5, MLH1, DMC1, GTF2H3, PER1, SMC5, TCEA1, and HERC2. The DRGS was independently associated with overall survival in both training and validation cohorts. The DRGS achieved higher accuracy than six previously reported multigene signatures for the prediction of prognosis in comparable cohorts. Furtherly, a nomogram incorporating DRGS and clinicopathological features showed improved predicting performance. Taken together, the DRGS was identified as a novel, robust, and effective prognostic indicator, which may refine the scheme of risk stratification and management in ESCC patients.

Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 529-529 ◽  
Author(s):  
Priyanka Sharma ◽  
William E. Barlow ◽  
Andrew K. Godwin ◽  
Laura A Knight ◽  
Steven M. Walker ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cox Regression ◽  
Early Stage ◽  
Selection Criterion ◽  
Tumor Infiltrating Lymphocytes ◽  
Gene Signature ◽  
Molecular Signature ◽  
Response To Chemotherapy ◽  
Damage Response

529 Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% & 82% in the lowest & highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.

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