scholarly journals DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 501 ◽  
Author(s):  
Leif Peterson ◽  
Tatiana Kovyrshina
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Statistical Significance ◽  
Candidate Gene Approach ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Genome Wide ◽  
A Genome ◽  
Dna Repair Gene ◽  
Repair Genes

Removal of the proliferation component of gene expression by proliferating cell nuclearantigen (PCNA) adjustment via statistical methods has been addressed in numerous survivalprediction studies for breast cancer and all cancers in the Cancer Genome Atlas (TCGA). Thesestudies indicate that the removal of proliferation in gene expression by PCNA adjustment removesthe statistical significance for predicting overall survival (OS) when gene selection is performed ona genome-wide basis. Since cancers become addicted to DNA repair as a result of forced cellularreplication, increased oxidation, and repair deficiencies from oncogenic loss or geneticpolymorphisms, we hypothesized that PCNA adjustment of DNA repair gene expression does notremove statistical significance for OS prediction. The rationale and importance of this translationalhypothesis is that new lists of repair genes which are predictive of OS can be identified to establishnew targets for inhibition therapy. A candidate gene approach was employed using TCGARNA-Seq data for 121 DNA repair genes in 8 molecular pathways to predict OS for 18 cancers.Statistical randomization test results indicate that after PCNA adjustment, OS could be predictedsignificantly by sets of DNA repair genes for 61% (11/18) of the cancers. These findings suggest thatremoval of the proliferation signal in expression by PCNA adjustment does not remove statisticalsignificance for predicting OS. In conclusion, it is likely that previous studies on PCNA adjustmentand survival were biased because genes identified through a genome-wide approach are stronglyco-regulated by proliferation.

scholarly journals DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers

2019 ◽  
Author(s):  
Leif Peterson ◽  
Tatiana Kovyrshina
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Gene Selection ◽  
P Value ◽  
Survival Prediction ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
A Genome ◽  
Dna Repair Gene ◽  
Repair Genes

Removal of the proliferation component of gene expression by PCNA adjustment has been addressed in numerous survival prediction studies for breast cancer and all cancers in the TCGA. These studies indicate that widespread co-regulation of proliferation upwardly biases survival prediction when gene selection is performed on a genome-wide basis. In addition, removal of the correlative effects of proliferation does not reduce the random bias associated with survival prediction using random gene selection. Since most cancers become addicted to DNA repair as a result of forced cellular replication, increased oxidation, and repair deficiencies from oncogenic loss or genetic polymorphisms, we pursued an investigation to remove the proliferation component of expression in DNA repair genes to determine survival prediction. This translational hypothesis-driven focus on DNA repair genes is directly amenable to finding new sets of DNA repair genes that could potentially be studied for inhibition therapy. Overall survival (OS) prediction was evaluated in 18 cancers by using normalized RNA-Seq data for 126 DNA repair genes with expression available in TCGA. Transformations for normality and adjustments for age at diagnosis, stage, and PCNA metagene expression were performed for all DNA repair genes. We also analyzed genomic event rates (GER) for somatic mutations, deletions, and amplification in driver genes and DNA repair genes. After performing empirical p-value testing with use of randomly selected gene sets, it was observed that OS could be predicted significantly by sets of DNA repair genes for 61% (11/18) of the cancers. Interestingly, PARP1 was not a significant predictor of survival for any of the 11 cancers. Results from cluster analysis of GERs indicates that the most opportunistic cancers for inhibition therapy may be AML, colorectal, and renal papillary, because of potentially less confounding due to lower GERs for mutations, deletions, and amplifications in DNA repair genes. However, the most opportunistic cancer for inhibition therapy is likely to be AML, since it showed the lowest GERs for mutations, deletions, and amplifications in DNA repair genes. In conclusion, our hypothesis-driven focus to target DNA repair gene expression adjusted for the PCNA metagene as a means of predicting OS in various cancers resulted in statistically significant sets of genes.

Occupational exposure to metal-rich particulate matter modifies the expression of repair genes in foundry workers

2021 ◽  
pp. 074823372110212
Author(s):  
Zahra Panjali ◽  
Omar Hahad ◽  
Fatemeh Rajabi ◽  
Saeid Maddah ◽  
Rezvan Zendehdel
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Dna Repair ◽  
Particulate Matter ◽  
Occupational Exposures ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Foundry Workers ◽  
Repair Genes

Foundry workers are exposed to numerous occupational health hazards, which may result in increased risk of cancer, respiratory disease, and other diseases. Oxidative stress is known to be involved in the pathogenesis of such diseases. The present study aimed to investigate the association between multiple occupational exposures in foundry workers and expression of deoxyribonucleic acid (DNA) repair genes as a biomarker of oxidative DNA damage. The study sample comprised 17 foundry workers and 27 matched control subjects. Expression of 8-oxoguanine DNA glycosylase-1 (OGG1), inosine triphosphate pyrophosphate (ITPA), and MutT homolog 1 (MTH1) in peripheral blood was examined using the real-time polymerase chain reaction method. Air sampling to determine exposure to metal-rich particulate matter and measurement of extremely low-frequency electromagnetic fields (ELF-EMFs) were conducted according to the National Institute for Occupational Safety and Health standard methods. Personal air sampling revealed that occupational exposure to particulate matter exceeded the threshold limit values (TLVs) in 76% of the workstations, whereas ELF-EMF exposure appeared to be lower than the TLV. ITPA was significantly upregulated in foundry workers compared with control subjects, whereas no significant difference was observed for OGG1 and MTH1. Moreover, ITPA was strongly and positively correlated with the concentration of metal-rich particulate matter in foundry workers. No significant correlation was found between ELF-EMF exposure and expression of DNA repair genes. DNA repair gene expression may be a sensitive biomarker for occupational exposures, which suggests an involvement of oxidative stress in metal-induced toxicity. Further studies are needed to determine the role of DNA repair gene expression in response to occupational/environmental hazards.

scholarly journals Lasting DNA Damage and Aberrant DNA Repair Gene Expression Profile Are Associated with Post-Chronic Cadmium Exposure in Human Bronchial Epithelial Cells

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 842 ◽  
Author(s):  
Heng Wee Tan ◽  
Zhan-Ling Liang ◽  
Yue Yao ◽  
Dan-Dan Wu ◽  
Hai-Ying Mo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Repair ◽  
Human Lung ◽  
Repair System ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Repair Genes ◽  
Cd Exposure

Cadmium (Cd) is a widespread environmental pollutant and carcinogen. Although the exact mechanisms of Cd-induced carcinogenesis remain unclear, previous acute/chronic Cd exposure studies have shown that Cd exerts its cytotoxic and carcinogenic effects through multiple mechanisms, including interference with the DNA repair system. However, the effects of post-chronic Cd exposure remain unknown. Here, we establish a unique post-chronic Cd-exposed human lung cell model (the “CR0” cells) and investigate the effects of post-chronic Cd exposure on the DNA repair system. We found that the CR0 cells retained Cd-resistant property even though it was grown in Cd-free culture medium for over a year. The CR0 cells had lasting DNA damage due to reduced DNA repair capacity and an aberrant DNA repair gene expression profile. A total of 12 DNA repair genes associated with post-chronic Cd exposure were identified, and they could be potential biomarkers for identifying post-chronic Cd exposure. Clinical database analysis suggests that some of the DNA repair genes play a role in lung cancer patients with different smoking histories. Generally, CR0 cells were more sensitive to chemotherapeutic (cisplatin, gemcitabine, and vinorelbine tartrate) and DNA damaging (H2O2) agents, which may represent a double-edged sword for cancer prevention and treatment. Overall, we demonstrated for the first time that the effects of post-chronic Cd exposure on human lung cells are long-lasting and different from that of acute and chronic exposures. Findings from our study unveiled a new perspective on Cd-induced carcinogenesis—the post-chronic exposure of Cd. This study encourages the field of post-exposure research which is crucial but has long been ignored.

scholarly journals DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers

2018 ◽  
Author(s):  
Leif E. Peterson ◽  
Tatiana Kovyrshina
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Cancer Survival ◽  
P Value ◽  
Survival Prediction ◽  
Dna Repair Genes ◽  
Driver Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Repair Genes

AbstractOne of the hallmarks of cancer is the existence of a high mutational load in driver genes, which is balanced by upregulation (downregulation) of DNA repair pathways, since almost complete DNA repair is required for mitosis. The prediction of cancer survival with gene expression has been investigated by many groups, however, results of a comprehensive re-evaluation of the original data adjusted by the PCNA metagene indicate that only a small proportion of genes are truly predictive of survival. However, little is known regarding the effect of the PCNA metagene on survival prediction specifically by DNA repair genes. We investigated prediction of overall survival (OS) in 18 cancers by using normalized RNA-Seq data for 126 DNA repair genes with expression available in TCGA. Transformations for normality and adjustments for age at diagnosis, stage, and PCNA metagene were performed for all DNA repair genes. We also analyzed genomic event rates (GER) for somatic mutations, deletions, and amplification in driver genes and DNA repair genes. After performing empirical p-value testing with use of randomly selected gene sets, it was observed that OS could be predicted significantly by sets of DNA repair genes for 61% (11/18) of the cancers. Pathway activation analysis indicates that in the presence of dysfunctional driver genes, the initial damage signaling and minor single-gene repair mechanisms may be abrogated, but with later pathway genes fully activated and intact. Neither PARP1 or PARP2 were significant predictors of survival for any of the 11 cancers. Results from cluster analysis of GERs indicates that the most opportunistic set of cancers warranting further study are AML, colorectal, and renal papillary, because of their lower GERs for mutations, deletions, and amplifications in DNA repair genes. However, the most opportunistic cancer to study is likely to be AML, since it showed the lowest GERs for mutations, deletions, and amplifications, suggesting that DNA repair pathway activation in AML is intact and unaltered genomically. In conclusion, our hypothesis-driven focus to target DNA repair gene expression adjusted for the PCNA metagene as a means of predicting OS in various cancers resulted in statistically significant sets of genes.Author summaryThe proliferating cell nuclear antigen (PCNA) protein is a homotrimer and activator of polymerase δ, which encircles DNA during transcription to recruit other proteins involved in replication and repair. In tumor cells, expression of PCNA is highly upregulated; however, PCNA-related activity is a normal process for DNA transcription in eukaryotes and therefore is not considered to play a central role in the selective genetic pressure associated with tumor development. Since PCNA is widely co-regulated with other genes in normal tissues, we developed workflow involving several functional transforms and regression models to “remove” the co-regulatory effect of PCNA on expression of DNA repair genes, and predicted overall cancer survival using DNA repair gene expression with and without removal of the PCNA effect. Other adjustments to survival prediction were employed, such as subject age at diagnosis and tumor stage. Random selection of gene sets was also employed for empirical p-value testing to determine the strength of the PCNA effect on DNA repair and overall survival adjustments. Since TCGA RNA-Seq data were used, we also characterized the frequency of deletions, amplifications, and somatic mutations in the DNA repair genes considered in order to observe which genomic events are the most frequent for the cancers evaluated.

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.

Homologous recombination deficiency (HRD) in patients with pancreatic cancer (PC) and response to chemotherapy.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 317-317 ◽  
Author(s):  
Safi Shahda ◽  
Kirsten Timms ◽  
Ashley Ibrahim ◽  
Julia E. Reid ◽  
Harvey M Cramer ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Locally Advanced ◽  
Response To Therapy ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Response To Chemotherapy ◽  
Mutation Data ◽  
Repair Genes

317 Background: Mutations or copy number abnormalities of genes involved in homologous recombination occur in PC. DNA-based measures of HRD have been developed and may help identify tumors with better response to DNA damaging agents. This study aimed to describe the mutation and HRD status of PC and determine their association with treatment response and outcome. Methods: This was a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PC. Patients were included if they received gemcitabine/nab-paclitaxel or FOLFIRINOX and had adequate follow up to assess survival and response to therapy. Tumor analysis generated a 3-biomarker (LOH, TAI, LST) HRD score and mutation data for 45 genes. Results: Ninety-one samples met inclusion criteria, 78 (15 FFPE and 63 FNA) generated mutation data. HRD analysis was successful for 57; the primary cause of failure low tumor %. The final analysis set consisted of 78 samples with mutation status, including 57 with HRD scores (range= 5 -61 (median=18,)). Six BRCA1/ 2 mutations were detected, 5 had high HRD scores, with 4 in the top decile (p=0.011). Other DNA repair gene mutations ( ATM=3, ATR=1, BRIP1=1 and FANCI=1) were detected, but most retained one functional allele and were not associated with HRD score. There was no statistically significant correlation between HRD score and response to FOLFIRINOX (OR per interquartile range = 1.40, p=0.32 adjusted for treatment). HRD score was not associated with PFS or OS. For FOLFIRINOX, median survival times for low vs. high HRD (dichotomized at the median) were 5.3 vs. 9.4 months PFS (p=0.049) and OS 12.3 vs. 11.3 months (p=0.89). For gemcitabine/nab-paclitaxel, mPFS was 6.1 vs. 4.6 months (p=0.88), and mOS was 14.4 vs. 11.4 months (p=0.29). Conclusions: Mutations in DNA repair genes occur in PC, and HRD scores can be generated in the majority of cases. HRD score was not significantly associated with higher response rate or prolonged survival in relation to FOLFIRINOX in this small non-randomized retrospective cohort. Larger studies to examine the association of mutations in DNA repair genes and HRD may be needed to detect significant associations.

Prognostic value of DNA repair gene based on stratification of gastric cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 12-12
Author(s):  
Jinjia Chang ◽  
Midie Xu ◽  
Hui Sun ◽  
Wenhua Li ◽  
Min Ye ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Repair ◽  
Clustering Analysis ◽  
Molecular Subtypes ◽  
Expression Profiles ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Key Genes ◽  
Repair Genes

12 Background: DNA repair genes can be used as prognostic biomarkers in many types of cancer. We aimed to identify prognostic DNA repair genes in patients with gastric cancer (GC) by systematically bioinformatic approaches using web-based database. Methods: Global gene expression profiles from altogether 1,325 GC patients’ samples from six independent datasets were included in the study. Clustering analysis was performed to screen potentially abnormal DNA repair genes related to the prognosis of GC, followed by unsupervised clustering analysis to identify molecular subtypes of GC. Characteristics and prognosis differences were analyzed among these molecular subtypes, and modular key genes in molecular subtypes were identified based on changes in expression correlation. Multivariate Cox proportional hazard analysis was used to find the independent prognostic gene. Kaplan-Meier method and log-rank test was used to estimate correlations of key DNA repair genes with GC patients’overall survival. Results: There were 57 key genes significantly associated to GC patients’ prognosis, and patients were stratified into three molecular clusters based on their expression profiles, in which patients in Cluster 3 showed the best survival (P < 0.05). After a three-phase training, test and validation process, the expression profile of 13 independent key DNA repair genes were identified can classify the prognostic risk of patients. Compared with patients with low-risk score, patients with high risk score in the training set had shorter overall survival (P < 0.0001). Furthermore, we verified equivalent findings by these key DNA repair genes in the test set (P < 0.0001) and the independent validation set (P = 0.0024). Conclusions: Our results suggest a great potential for the use of DNA repair gene profiling as a powerful marker in prognostication and inform treatment decisions for GC patients.

A Polymorphism Study on Detoxification and DNA Repair Genes in 700 MDS Patients Demonstrates An Association Between Genotype and An Aberrant Karyotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2690-2690
Author(s):  
C. Seedhouse ◽  
Stephanie Fischer ◽  
Christina Ganster ◽  
Christa Fonatsch ◽  
Peter Valent ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genetic Stability ◽  
Genetic Instability ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Xrcc3 Thr241met ◽  
Repair Genes

Abstract The maintenance of genetic stability within haematopoietic stem cells is essential for normal haematopoiesis and this is emphasised by the association of leukemias and myelodysplastic syndromes (MDS) with genetic instability. DNA is normally protected from damage via a number of complex pathways including detoxification and DNA repair pathways. Inefficient processing of DNA damage may result in an increased susceptibility to leukemia and MDS. Genetic polymorphisms exist in many genes within the DNA damage processing pathways, some of which affect the cells ability to maintain genetic stability. We have studied polymorphisms in the homologous DNA repair genes RAD51 (RAD51-g135c) and XRCC3 (XRCC3-Thr241Met) and the detoxification gene GSTM1 (deletion polymorphism) in more 700 MDS samples. The GSTM1 polymorphism was studied using PCR, and the RAD51 and XRCC3 genotypes were assayed simultaneously using a SNaPshot technique. The genotype distributions of RAD51-g135c and GSTM1 did not differ significantly from those reported in the literature. However the distribution of the XRCC3-Thr241Met polymorphism was found to be significantly different, with an over-representation of the variant Met allele, when compared to previously published frequencies in control populations1 (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.3–2.6, p&lt;0.001). Whilst the presence of a single polymorphic variant may display only a subtle effect, polymorphic variants of more than one gene involved in the same pathway are likely to be biologically important with respect to the cellular ability to maintain genetic integrity and hence may play a role in MDS pathogenesis. RAD51, XRCC3 and GSTM1 genotypes were therefore studied in combined analyses. Similar to studies in AML1, the double DNA repair gene variant (RAD51–135c/XRCC3–241) was over-represented in MDS compared to a control population (OR 3.8; 95% CI 1.6–9.3, p=0.002). The triple variant genotype (RAD51–135c/XRCC3–241Met/GSTM1-null) was associated with a further increased risk of MDS (OR 13.5; 95% CI 1.8–102.8, p=0.01). More detailed analysis was undertaken to compare the polymorphic distributions in MDS with aberrant karyotypes. When the single genes were assessed, the GSTM1 null genotype was the only one to be over-represented in MDS with an aberrant karyotype compared to MDS with a normal karyotype (OR 1.6; 95% CI 1.05–2.5). Interestingly, when analysing the genotypes with respect to the XRCC3/RAD51 combined genotypes the presence of homozygous wild type alleles of one DNA repair gene matched with the presence of a variant allele of the other DNA repair gene is significantly protective against karyotypic abnormalities when compared to the double WT patients (OR 0.29; 95% CI 0.29–0.78; p=0.003). Collectively these results suggest that polymorphisms in genes which process DNA damage play a significant role in MDS pathogenesis and may also contribute to genetic instability in MDS.

scholarly journals Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Reham Abdel-Wahab ◽  
Timothy A. Yap ◽  
Russell Madison ◽  
Shubham Pant ◽  
Matthew Cooke ◽  
...  
Keyword(s):  
Dna Repair ◽  
Gallbladder Cancer ◽  
Genomic Profiling ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Repair Genes ◽  
Cell Death Protein

AbstractDNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (< 5.5 mutations/Mb), intermediate (5.5–19.5 mutations/Mb), and high (≥ 19.5 mutations/Mb). We assessed MSI status and PD-1 & PD-L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identified in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were significantly associated with high TMB (P = 0.0005 and 0.0001, respectively). Tumor PD-L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.

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