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Mutation Research Aug 2012DNA suffers from a wide range of damage, both from extracellular agents and via endogenous mechanisms. Damage of DNA can lead to cancer and other diseases. Therefore, it... (Review)
Review
DNA suffers from a wide range of damage, both from extracellular agents and via endogenous mechanisms. Damage of DNA can lead to cancer and other diseases. Therefore, it is plausible that sequence variants in DNA repair genes are involved in cancer development. A recent systematic review and meta-analysis, based on the "Venice criteria", showed that out of 241 associations investigated, only three resulted to have a strong grade of cumulative evidence. These associations were: two SNPs rs1799793 and rs13181 in the ERCC2 gene and lung cancer (recessive model) and rs1805794 in the NBN gene and bladder cancer (dominant model). An update of this meta-analysis has been performed in the present paper, and we found partially inconsistent results. Inconsistencies in the literature are thus far not easy to explain. In addition, none of the cancer genome-wide association studies (GWAs) published so far showed highly statistically significant associations for any of the common DNA repair gene variants, in such a way as to place DNA repair genes among the top 10-20 hits identified in GWAs. Though this suggests that it is unlikely that DNA repair gene polymorphisms per se play a major role, a clarification of the discrepancies in the literature is needed. Also, gene/environment and gene/lifestyle interactions for the carcinogenic mechanisms involving DNA repair should be investigated more systematically and with less classification error. Finally, the combined effect of multiple SNPs in several genes in one or more relevant DNA repair pathways could have a greater impact on pathological phenotypes than SNPs in single genes, but this has been investigated only occasionally.
Topics: DNA Repair; Gene-Environment Interaction; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Meta-Analysis as Topic; Neoplasms; Polymorphism, Genetic
PubMed: 21864546
DOI: 10.1016/j.mrfmmm.2011.07.013 -
Molecular Oncology Feb 2024In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA... (Review)
Review
In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA forms distinct cluster, separate from other IDH-mutant gliomas, including IDH-mutant gliomas with secondary mismatch repair (MMR) deficiency. In the published cohort, three patients received treatment with an immune checkpoint blocker (ICB), yet none exhibited a response, which aligns with existing knowledge about the decreased immunogenicity of IDH-mutant gliomas in comparison to IDH-wildtype. In the case of PMMRDIA, the inherent resistance to the standard-of-care temozolomide caused by MMR deficiency is an additional challenge. It is known that a gain-of-function mutation of IDH1/2 genes produces the oncometabolite R-2-hydroxyglutarate (R-2-HG), which increases DNA and histone methylation contributing to the characteristic glioma-associated CpG island methylator phenotype (G-CIMP). While other factors could be involved in remodeling the tumor microenvironment (TME) of IDH-mutant gliomas, this systematic review emphasizes the role of R-2-HG and the subsequent G-CIMP in immune suppression. This highlights a potential actionable pathway to enhance the response of ICB, which might be relevant for addressing the unmet therapeutic challenge of PMMRDIA.
PubMed: 38339779
DOI: 10.1002/1878-0261.13598 -
Medicina Oral, Patologia Oral Y Cirugia... Jun 2024The DNA mismatch repair (MMR) system serves as a sophisticated guardian of the precise functioning of the human genome. Dysregulation within this system is linked to the...
BACKGROUND
The DNA mismatch repair (MMR) system serves as a sophisticated guardian of the precise functioning of the human genome. Dysregulation within this system is linked to the oncogenesis process. Reduced expression of MMR system proteins identified in salivary gland tumors (SGTs) suggests an increased risk of tumoral occurrence. This study aims to analyze the expression of MMR proteins in SGTs and discuss the relevance of this association to the development of these neoplasms.
MATERIAL AND METHODS
This review was conducted following the PRISMA guidelines and was registered in PROSPERO (CRD42023465590). A comprehensive search of the PubMed/MEDLINE, Web of Science, Scopus, Embase, and ProQuest (non-peer reviewed platform) was performed to answer the question "Do DNA MMR system proteins exhibit expression in SGTs?". The methodological quality of the selected studies was assessed using the JBI's Critical Appraisal Tool.
RESULTS
A total of 142 patients with benign SGTs and 84 with malignant SGTs were included in this review. The literature analysis showed a notable reduction in the expression of DNA MMR system proteins (hHMS2, hMLH1, hMSH3 and hMSH6) in the percentage of marked cells.
CONCLUSIONS
The reduction in the expression of the DNA MMR system proteins suggests an interesting correlation with the development of malignant and benign SGTs. Nevertheless, further investigations are warranted to better clarify the precision of measuring biomarker protein expression.
PubMed: 38907641
DOI: 10.4317/medoral.26647 -
BioMed Research International 2022Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of UV radiation-induced damage repair that is characterized by photosensitivity and a propensity for... (Review)
Review
BACKGROUND
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of UV radiation-induced damage repair that is characterized by photosensitivity and a propensity for developing, among many others, skin cancers at an early age. This systematic review focused on the correlation between the clinical, pathological, and genetic aspects of XP and skin cancer.
METHODS
A systematic review was conducted through a literature search of online databases PubMed, Cochrane Library, SciELO, and Google Scholar. Search terms were "Xeroderma pigmentosum", "XP", "XPC", "Nucleotide excision repair", "NER", "POLH", "Dry pigmented skin", and "UV sensitive syndrome" meshed with the terms "Skin cancer", "Melanoma", and "NMSC".
RESULTS
After 504 abstracts screening, 13 full-text articles were assessed for eligibility, and 3 of them were excluded. Ten articles were selected for qualitative assessment.
CONCLUSIONS
Patients with XP usually suffer shorter lives due to skin cancer and neurodegenerative disease. Deletion/alteration of a distinct gene allele can produce different types of cancer. The XPC and XP-E variants are more likely to have skin cancer than patients in other complement groups, and the most common cause of death for these patients is skin cancer (metastatic melanoma or invasive SCC). Still, aggressive preventative measures to minimize UV radiation exposure can retard the course of the disease and improve the quality of life.
Topics: DNA Repair; Humans; Ichthyosis; Melanoma; Neurodegenerative Diseases; Quality of Life; Skin Neoplasms; Ultraviolet Rays; Xeroderma Pigmentosum
PubMed: 35898688
DOI: 10.1155/2022/8549532 -
Antioxidants & Redox Signaling Apr 20168-Hydroxy-2-deoxyguanosine (8-OHdG) is generated after the repair of ROS-mediated DNA damages and, thus, is one of the most widely recognized biomarkers of oxidative... (Meta-Analysis)
Meta-Analysis Review
SIGNIFICANCE
8-Hydroxy-2-deoxyguanosine (8-OHdG) is generated after the repair of ROS-mediated DNA damages and, thus, is one of the most widely recognized biomarkers of oxidative damage of DNA because guanosine is the most oxidized among the DNA nucleobases. In several pathological conditions, high urinary levels of oxidized DNA-derived metabolites have been reported (e.g., cancer, atherosclerosis, hypertension, and diabetes).
RECENT ADVANCES
Even if published studies have shown that DNA damage is significantly associated with the development of atherosclerosis, the exact role of this damage in the onset and progression of this pathology is not fully understood, and the association of oxidative damage to DNA with cardiovascular disease (CVD) still needs to be more extensively investigated. We performed a meta-analysis of the literature to investigate the association among 8-OHdG levels and CVD.
CRITICAL ISSUES
Fourteen studies (810 CVD patients and 1106 controls) were included in the analysis. We found that CVD patients showed higher 8-OHdG levels than controls (SMD: 1.04, 95%CI: 0.61, 1.47, p < 0.001, I(2) = 94%, p < 0.001). The difference was confirmed both in studies in which 8-OHdG levels were assessed in urine (MD: 4.43, 95%CI: 1.71, 7.15, p = 0.001) and in blood samples (MD: 1.42, 95%CI: 0.64, 2.21, p = 0.0004). Meta-regression models showed that age, hypertension, and male gender significantly impacted on the difference in 8-OHdG levels among CVD patients and controls.
FUTURE DIRECTIONS
8-OHdG levels are higher in patients with CVD than in controls. However, larger prospective studies are needed to test 8-OHdG as a predictor of CVD.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Deoxyguanosine; Humans; Oxidation-Reduction; Oxidative Stress; Prognosis; Publication Bias; Regression Analysis
PubMed: 26650622
DOI: 10.1089/ars.2015.6508 -
Oral Oncology Jun 2015Our aim of the study was to investigate the precise relationship of repair cross-complementation group 1 (ERCC1) expression and the survival as well as objective... (Meta-Analysis)
Meta-Analysis Review
The roles of excision repair cross-complementation group1 in objective response after cisplatin-based concurrent chemoradiotherapy and survival in head and neck cancers: a systematic review and meta-analysis.
Our aim of the study was to investigate the precise relationship of repair cross-complementation group 1 (ERCC1) expression and the survival as well as objective response rate to cisplatin-based concurrent chemoradiotherapy (CCRT) and a meta-analysis was conducted to analysis ERCC1's prognostic roles in head and neck cancer. A search based on published articles in PubMed, Embase and CKNI database (up to Oct 15, 2014) to find eligible studies meeting eligibility criteria and then a meta-analysis was conducted to assess the outcomes in head and neck squamous cell carcinomas (HNSCC) patients with different ERCC1 expression. The principle outcomes were hazard ratio (HR) for survival analysis and relative risks (RR) for objective response. Fixed or random model was used for calculation according to the heterogeneity. The results showed that 9 studies involving 568 patients met the inclusion criteria. Low/negative expression of ERCC1 was associated with longer overall survival (OS) and profession-free survival (PFS) after receiving cisplatin-based CCRT therapy (HR 0.38; 95% confidence interval (CI) 0.21-0.63; P<0.001 and HR 0.37; 95%CI 0.21-0.63; P<0.001). And there was no significant difference discovered in objective response rate between low/negative and high/positive ERCC1 expression (RR 1.19; 95%CI 1.00-1.43; P=0.06). Evidence of modest heterogeneity was found between ERCC1 expression and OS (I(2)=48.8%, P<0.05) and subgroup analysis was performed based on ethnicity, variable methods and primary tumor location. The conclusion is that ERCC1 might be the one of adverse prognostic factors affecting the survival time and objective response to cisplatin-based chemoradiotherap due to its drug-resistance characteristics.
Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; DNA-Binding Proteins; Disease-Free Survival; Endonucleases; Head and Neck Neoplasms; Humans; Prognosis
PubMed: 25857670
DOI: 10.1016/j.oraloncology.2015.03.009 -
BMC Cancer Jan 2011The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with... (Meta-Analysis)
Meta-Analysis Review
O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction.
BACKGROUND
The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled. The aim of this study was to perform a systematic review and meta-analysis of the correlation between IHC and MSP.
METHODS
A computer-aided search of MEDLINE (1950-October 2009), EBSCO (1966-October 2009) and EMBASE (1974-October 2009) was performed for relevant publications. Studies meeting inclusion criteria were those comparing MGMT protein expression by IHC with MGMT promoter methylation by MSP in the same cohort of patients. Methodological quality was assessed by using the QUADAS and STARD instruments. Previously published guidelines were followed for meta-analysis performance.
RESULTS
Of 254 studies identified as eligible for full-text review, 52 (20.5%) met the inclusion criteria. The review showed that results of MGMT protein expression by IHC are not in close agreement with those obtained with MSP. Moreover, type of tumour (primary brain tumour vs others) was an independent covariate of accuracy estimates in the meta-regression analysis beyond the cut-off value.
CONCLUSIONS
Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably.
Topics: Brain Neoplasms; DNA Methylation; Humans; Immunohistochemistry; Neoplasms; O(6)-Methylguanine-DNA Methyltransferase; Polymerase Chain Reaction; Prognosis; Promoter Regions, Genetic
PubMed: 21269507
DOI: 10.1186/1471-2407-11-35 -
The Cochrane Database of Systematic... Jun 2010Ovarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide.Three-quarters of women present when the disease has... (Review)
Review
BACKGROUND
Ovarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide.Three-quarters of women present when the disease has spread through-put the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy, with or without taxanes. Although initial responses to chemotherapy are often good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy agents. Increased understanding about the molecular basis of ovarian cancer has lead to the development of novel agents, which work in different ways to conventional chemotherapy. These include DNA-repair pathway inhibitors, the commonest of which are the PARP (poly (ADP-ribose) polymerase) inhibitors. It is therefore important to compare their effectiveness and side effects of these novel agents to assess their role in the treatment of advanced ovarian cancer, especially as treatment of advanced disease is aiming to improve length of survival and quality of life (QoL).
OBJECTIVES
To compare the effectiveness and harmful effects of interventions, which inhibit DNA-repair pathways, in the treatment of ovarian cancer.
SEARCH STRATEGY
RCTs were identified by searching The Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2009), The Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, MEDLINE (1990 to June 2009), EMBASE (1990 to June 2009), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature.
SELECTION CRITERIA
Adult women with histologically proven ovarian cancer who were randomised to treatment groups which either compared DNA-repair pathway inhibitors with no treatment or DNA-repair pathway inhibitors together with conventional chemotherapy compared with conventional chemotherapy alone.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. Searches for additional data and information were also performed by two independent review authors. No trials were found and therefore no data were analysed, so only information on excluded references was collected.
MAIN RESULTS
The search strategy identified 473 unique references of which 461 were excluded on the basis of title and abstract. The remaining 12 articles were retrieved in full, but none satisfied the inclusion criteria. However, two ongoing randomised phase II clinical trials were identified from the clinical trials databases that met our inclusion criteria, but no preliminary data were available.
AUTHORS' CONCLUSIONS
There are to date no published RCT data on the effectiveness and side effects of DNA-repair pathways inhibitors used alone or in association with conventional chemotherapy in the treatment of ovarian cancer. On-going trials have been identified and results are awaited and will be included in future updates of this review.
Topics: Adult; Antineoplastic Agents; DNA Repair; Female; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 20556786
DOI: 10.1002/14651858.CD007929.pub2 -
Molecular Cancer Research : MCR Jun 2021Mucosal melanoma is a rare subtype of melanoma. To date, there has been no comprehensive systematic collation and statistical analysis of the aberrations and aggregated... (Meta-Analysis)
Meta-Analysis
Mucosal melanoma is a rare subtype of melanoma. To date, there has been no comprehensive systematic collation and statistical analysis of the aberrations and aggregated frequency of driver events across multiple studies. Published studies using whole genome, whole exome, targeted gene panel, or individual gene sequencing were identified. Datasets from these studies were collated to summarize mutations, structural variants, and regions of copy-number alteration. Studies using next-generation sequencing were divided into the "main" cohort ( = 173; fresh-frozen samples), "validation" cohort ( = 48; formalin-fixed, paraffin-embedded samples) and a second "validation" cohort comprised 104 tumors sequenced using a targeted panel. Studies assessing mutations in , and were summarized to assess hotspot mutations. Statistical analysis of the main cohort variant data revealed , and as significantly mutated genes. and mutations occurred more commonly in lower anatomy melanomas and in the upper anatomy. , and were commonly affected by chromosomal copy loss, while , and were commonly amplified. Further notable genomic alterations occurring at lower frequencies indicated commonality of signaling networks in tumorigenesis, including MAPK, PI3K, Notch, Wnt/β-catenin, cell cycle, DNA repair, and telomere maintenance pathways. This analysis identified genomic aberrations that provide some insight to the way in which specific pathways may be disrupted. IMPLICATIONS: Our analysis has shown that mucosal melanomas have a diverse range of genomic alterations in several biological pathways. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/6/991/F1.large.jpg.
Topics: Biomarkers, Tumor; DNA Copy Number Variations; Genetic Predisposition to Disease; Genomics; Humans; Melanoma; Mutation; Signal Transduction; Skin Neoplasms; Whole Genome Sequencing
PubMed: 33707307
DOI: 10.1158/1541-7786.MCR-20-0839 -
Medical Oncology (Northwood, London,... Feb 2015The oxyguanine glycosylase 1 (OGG1) gene has an important role in DNA repair, and the polymorphism of the gene may alter cancer susceptibility. This study aims to... (Meta-Analysis)
Meta-Analysis Review
The oxyguanine glycosylase 1 (OGG1) gene has an important role in DNA repair, and the polymorphism of the gene may alter cancer susceptibility. This study aims to examine the association between the OGG1 Ser326Cys polymorphism and cancer risk based on meta-analysis. Relevant studies were identified through a search of PubMed and Weipu databases, and a total of 109 studies including 111 comparisons containing 34,041 cases and 42,730 controls were enrolled. Overall, significant association was observed between OGG1 Ser326Cys polymorphism and cancer risk in all genetic models except for heterozygote model (Cys/Cys + Cys/Ser vs Ser/Ser: OR 1.071, 95 % CI 1.019-1.125; Cys/Cys vs Cys/Ser + Ser/Ser: OR 1.159, 95 % CI 1.076-1.248; Cys/Cys vs Ser/Ser: OR 1.202, 95 % CI 1.105-1.308). In stratified analysis by cancer type, significantly increased cancer risk was observed in digestive system cancer, head and neck cancer and lung cancer. For gynecologic cancer, significantly increased cancer risk was also observed in homozygote model (OR 1.974, 95 % CI 1.254-3.107). In addition, in stratified analysis by ethnicities, increased cancer risk was found in Asians (Cys/Cys vs Cys/Ser + Ser/Ser: OR 1.195, 95 % CI 1.088-1.313; Cys/Cys + Cys/Ser vs Ser/Ser: OR 1.115, 95 % CI 1.045-1.190; Cys/Cys vs Ser/Ser: OR 1.273, 95 % CI 1.149-1.410). The OGG1 Ser326Cys polymorphism may be a risk factor for cancers of lung, digestive system and head and neck.
Topics: DNA Glycosylases; Genetic Predisposition to Disease; Genotype; Humans; Neoplasms; Polymorphism, Single Nucleotide
PubMed: 25588927
DOI: 10.1007/s12032-014-0472-z