Excision Repair Cross-complementing Research Articles

The chromatin remodeler ERCC6 and the histone chaperone NAP1 are involved in apurinic/apyrimidinic endonuclease-mediated DNA repair.

During base excision repair (BER), the apurinic or apyrimidinic (AP) site serves as an intermediate product following base excision. In plants, APE-redox protein (ARP) represents the major AP site of cleavage activity. Despite the well-established understanding that the nucleosomal structure acts as a barrier to various DNA-templated processes, the regulatory mechanisms underlying BER at the chromatin level remain elusive, especially in plants. In this study, we identified plant chromatin remodeler Excision Repair Cross-Complementing protein group 6 (ERCC6) and histone chaperone Nucleosome Assembly Protein 1 (NAP1) as interacting proteins with ARP. The catalytic ATPase domain of ERCC6 facilitates its interaction with both ARP and NAP1. Additionally, ERCC6 and NAP1 synergistically contribute to nucleosome sliding and exposure of hindered endonuclease cleavage sites. Loss-of-function mutations in Arabidopsis (Arabidopsis thaliana) ERCC6 or NAP1 resulted in arp-dependent plant hypersensitivity to 5-fluorouracil (5-FU), a toxic agent inducing BER, and the accumulation of AP sites. Furthermore, similar protein interactions are also found in yeast cells, suggesting a conserved recruitment mechanism employed by the AP endonuclease to overcome chromatin barriers during BER progression.

Tumor microenvironment-activated hollow vanadium-based nanoplatform for precise therapy of lung cancer through synergistically reversing cisplatin resistance

The resistance and side effect of cisplatin (CDDP) were still great challenges for highly efficient therapy of lung cancer in clinic. The studies indicated that the CDDP resistance mainly involved GSH-mediated inactivation and the damaged DNA repair. Herein, a novel vanadium-based nanoplatform was designed via platelet-derived growth factor receptor-β (PDGFR-β)-recognizing cyclic peptide (PDGFB)-labeled liposomes coating onto the hollow vanadium-doped mesoporous silica nanoparticle (HVMSN) loaded Pt (IV) prodrugs (pLi-HVMSN-Pt). This nanoplatform actively targeted tumor tissue, and then effectively responded to weakly acidic and high GSH of tumor microenvironment, making Pt (IV) prodrugs and vanadium ions be precisely delivered and intelligently released. Moreover, the vanadium ions significantly downregulated the expression of glutamyl cysteine ligase (GCL) and excision repair cross-complementing 1 (ERCC1), which inhibited the synthesis of GSH in cells and the damaged DNA repair. These synergistic actions dramatically increased the sensitivity of tumor cells to Pt-based drug, and then reversed CDDP resistance. Furthermore, in vivo experiment results demonstrated highly efficient suppression of tumor growth induced by the pLi-HVMSN-Pt. Therefore, this work provided a novel strategy for reversing CDDP-resistance and the precise therapy of lung cancer.

Noise Stress Abrogates Structure-Specific Endonucleases within the Mammalian Inner Ear.

Nucleotide excision repair (NER) is a multistep biochemical process that maintains the integrity of the genome. Unlike other mechanisms that maintain genomic integrity, NER is distinguished by two irreversible nucleolytic events that are executed by the xeroderma pigmentosum group G (XPG) and xeroderma pigmentosum group F (XPF) structure-specific endonucleases. Beyond nucleolysis, XPG and XPF regulate the overall efficiency of NER through various protein-protein interactions. The current experiments evaluated whether an environmental stressor could negatively affect the expression of Xpg (Ercc5: excision repair cross-complementing 5) or Xpf (Ercc4: excision repair cross-complementing 4) in the mammalian cochlea. Ubiquitous background noise was used as an environmental stressor. Gene expression levels for Xpg and Xpf were quantified from the cochlear neurosensory epithelium after noise exposure. Further, nonlinear cochlear signal processing was investigated as a functional consequence of changes in endonuclease expression levels. Exposure to stressful background noise abrogated the expression of both Xpg and Xpf, and these effects were associated with pathological nonlinear signal processing from receptor cells within the mammalian inner ear. Given that exposure to environmental sounds (noise, music, etc.) is ubiquitous in daily life, sound-induced limitations to structure-specific endonucleases might represent an overlooked genomic threat.

Abstract A030: DNA repair gene polymorphism(s): Association with relapse of oral squamous cell carcinoma

Abstract Differences in DNA repair capacity have been linked to the risk and prognosis of cancer. In specific types of cancer, certain variations known as Single Nucleotide Polymorphisms (SNPs) within DNA repair genes can influence the effectiveness of treatments. This phenomenon has been observed in patients with Oral Squamous Cell Carcinoma (OSCC), especially in those undergoing chemotherapy and radiation therapy. One such gene, Excision Repair Cross-Complementation 5 (ERCC5), contains a SNP (rs17655) G>C, leading to a missense variation and a change in amino acid from D to H. This variation has been noted in various cancer types. Hence, this study aimed to investigate the presence of this DNA repair gene polymorphism (rs17655) and its association with OSCC. To achieve this goal, blood samples were collected from OSCC patients exposed to chemotherapy and radiation therapy, as well as from OSCC patients not exposed to these treatments, following approval from the relevant institutional review committees. Informed consent was obtained from 100 patients, and an equal number of age and gender-matched controls. Genomic DNA was extracted using the salting-out method and analyzed for quality and quantity through agarose gel electrophoresis and nanodrop spectrophotometry. Primers were designed using online primer designing software. Genetic variations were identified using Tetra Primers-Amplifies Refractory Mutation System Polymerase Chain Reaction (t-ARMS PCR), and the amplified products were visualized via agarose gel electrophoresis. The genotypic frequency analysis of rs17655 revealed a higher prevalence of the homozygous mutant type (CC) in the blood samples of OSCC patients, both exposed and non-exposed to chemotherapy and radiation therapy. In contrast, the homozygous wild type (GG) was more prevalent among the control group. Statistical analysis, including a chi-square test (χ 2 = 36.76, p < 0.001) and odds ratio (10.27), demonstrated a significant association between the rs17655 polymorphism and oral squamous cell carcinoma, indicating an increased risk of OSCC due to this genetic variation. These genomic variants have the potential to serve as biomarkers for predicting clinical outcomes in OSCC patients undergoing chemotherapy and radiotherapy. Citation Format: Umaiya Abdali, Saima Saleem. DNA repair gene polymorphism(s): Association with relapse of oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A030.

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin.

Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (ERCC1 and ERCC2) leads to improved patient outcomes after treatment with Pt-based chemotherapies. Although most NER gene alterations found in patient tumors are missense mutations, the impact of mutations in the remaining nearly 20 NER genes is unknown. Towards this goal, we previously developed a machine learning strategy to predict genetic variants in an essential NER protein, Xeroderma Pigmentosum Complementation Group A (XPA), that disrupt repair. In this study, we report in-depth analyses of a subset of the predicted variants, including in vitro analyses of purified recombinant protein and cell-based assays to test Pt agent sensitivity in cells and determine mechanisms of NER dysfunction. The most NER deficient variant Y148D had reduced protein stability, weaker DNA binding, disrupted recruitment to damage, and degradation. Our findings demonstrate that tumor mutations in XPA impact cell survival after cisplatin treatment and provide valuable mechanistic insights to improve variant effect prediction. Broadly, these findings suggest XPA tumor variants should be considered when predicting chemotherapy response.

Prognostic Significance of Excision Repair Cross-Complementation Group 1 on Circulating Tumor Cells for Nasopharyngeal Carcinoma.

Liquid biopsy, including the detection of circulating tumor cells (CTCs), has emerged as a promising tool for cancer diagnosis and monitoring. However, the prognostic value of CTCs in nasopharyngeal carcinoma (NPC) remains unclear due to the lack of phenotypic characterization. The expression of Excision Repair Cross-Complementation Group 1 (ERCC1) and CTCs epithelial-mesenchymal transition (EMT) have been associated with treatment efficacy. In this study, we aimed to evaluate the prognostic significance of ERCC1 expression on CTCs and their EMT subtypes before treatment in NPC. We retrospectively analyzed 108 newly diagnosed locally advanced NPC patients who underwent CanPatrol™ CTC testing between November 2018 and November 2021. CTCs were counted and classified into epithelial, epithelial-mesenchymal hybrid, and mesenchymal subtypes. ERCC1 expression was divided into negative and positive groups. Clinical features and survival outcomes were analyzed. The positive rate of CTCs was 92.6% (100/108), with an ERCC1 positivity rate of 74% (74/100). Further analysis of the subtypes showed that positive ERCC1 on mesenchymal CTCs was associated with a later N stage (P = .01). Positive ERCC1 expression was associated with poor overall survival (OS; P = .039) and disease-free survival (DFS; P = .035). Further analysis of subtypes showed that the positive ERCC1 on mesenchymal-type CTCs was associated with poor OS (P = .012) and metastasis-free survival (MFS; P = .001). Our findings suggest that ERCC1 expression on CTCs may serve as a new prognostic marker for NPC patients. Evaluating CTCs subtypes may become an auxiliary tool for personalized and precise treatment.

Role of rs873601 Polymorphisms in Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

Lung cancer is still the most lethal malignancy in the world, according to the report of Cancer Statistics in 2021. Platinum-based chemotherapy combined with immunotherapy is the first-line treatment in lung cancer patients. However, the 5-year survival rate is always affected by the adverse reactions and drug resistance caused by platinum-based chemotherapy. DNA damage and repair system is one of the important mechanisms that can affect the response to chemotherapy and clinical outcomes in lung cancer patients. The objective of this study is to find the relationship between the polymorphisms of DNA repair genes with the prognosis of platinum-based chemotherapy in lung cancer patients. We performed genotyping in 17 single nucleotide polymorphisms (SNPs) of Excision Repair Cross-Complementation group (ERCC) genes and X-ray Repair Cross-Complementing (XRCC) genes of 345 lung cancer patients via Sequenom MassARRAY. We used Cox proportional hazard models, state, and plink to analyze the associations between SNPs and the prognosis of lung cancer patients. We found that the ERCC5 rs873601 was associated with the overall survival time in lung cancer patients treated with platinum-based chemotherapy (p = 0.031). There were some polymorphisms that were related to the prognosis in specific subgroups of lung cancer. Rs873601 showed a great influence on the prognosis of patients more than 55 years, Small Cell Lung Cancer (SCLC), and smoking patients. Rs2444933 was associated with prognosis in age less than 55 years, SCLC, metastasis, and stage III/IV/ED patients. Rs3740051 played an important role in the prognosis of SCLC and metastasis patients. Rs1869641 was involved in the prognosis of SCLC patients. Rs1051685 was related to the prognosis in non-metastasis patients. The ERCC5 rs873601 (G>A) was a valuable biomarker for predicting the prognosis in lung cancer patients treated with platinum-based chemotherapy.

BRCA1 expression and its combined low expression with PARP1 and ERCC1 predict chemotherapeutic response in ovarian cancer

Objective: This study aimed to evaluate the associations of immunohistochemical expressions of various deoxyribonucleic acid repair proteins, either individually or combined, with the response to platinum-based chemotherapy and overall survival in epithelial ovarian cancer.Material and Methods: This retrospective cohort study included patients with epithelial ovarian cancer who were treated by primary cytoreductive surgery with adjuvant platinum-based chemotherapy at Songklanagarind Hospital between January 2008 and December 2019. Immunohistochemistry analysis of breast cancer type 1 (BRCA1), poly (ADP-ribose) polymerase 1 (PARP1), X-ray repair cross-complementing 1 (XRCC1), and excision repair cross-complementation group 1 (ERCC1) expression was performed. Logistic regression was used to evaluate factors associated with chemotherapeutic response and Cox regression was applied for survival analysis.Results: Chemotherapeutic response was achieved in 205 of 249 patients (82.3%). Low BRCA1 expression was associated with good response (odds ratio [OR] 5.01, 95% confidence interval [CI] 1.78–14.1) and favorable overall survival (hazard ratio 0.61, 95% CI 0.38–0.98). PARP1, XRCC1, and ERCC1 showed no significant predictive or prognostic roles; however, combined low expression of PARP1/BRCA1 (OR 7.62, 95% CI 1.69–34.31) and ERCC1/BRCA1 (OR 6.98, 95% CI 1.5–32.52) additively enhanced response compared to high/high expressions.Conclusion: This study provides evidence that epithelial ovarian cancer (EOC) with low BRCA1 expression is more likely to be responsive to platinum-based therapy and is associated with favorable overall survival compared to tumors with high BRCA1 expression. The study supports a potential therapeutic strategy involving co-depletion of PARP1/BRCA and ERCC1/BRCA1 expression, although additional studies are needed.

Polymorphisms in ERCC1, ERCC4 and ERCC5 genes as biomarkers of susceptibility for pesticide-induced DNA damage in North-West Indian agricultural workers

BackgroundOccupational pesticides exposure has raised health concerns due to genotoxicity and accumulation of DNA damage. Polymorphisms in genes encoding enzymes involved in nucleotide excision repair (NER) may affect the individual’s susceptibility to pesticide toxicity.MethodsThis study evaluates the association of excision repair cross complementation group 1 (ERCC1) (8092 C > A, 3’UTR, rs3212986) and ERCC1 (19007 C > T, Asn118Asn, rs11615), ERCC4 (1244 G > A, Arg415Gln, rs1800067) and ERCC5 (3507 G > C, Asp1104His, rs17655) polymorphisms with pesticide-induced DNA damage in North-West Indian agricultural workers. The study population comprised 225 agricultural workers exposed to pesticides and 225 non-exposed controls.ResultsOur study demonstrate that exposed workers carrying variant ERCC1 8092AA genotype showed higher total comet DNA migration (p = 0.015) as well as increased frequency of cells showing DNA migration (p = 0.027). Exposed agricultural workers with variant ERCC4 1244AA (415Gln/Gln) and ERCC5 3507CC (1104His/His) genotypes exhibited elevation in total comet DNA migration (p < 0.01). However, genotypes of ERCC1 19007 C > T (Asn118Asn) showed no association with total comet DNA migration (p = 0.963), frequency of cells showing DNA migration (p = 0.423) as well as mean tail length (p = 0.432).ConclusionERCC1, ERCC4 and ERCC5 polymorphisms influence DNA damage and can be used as biomarkers of susceptibility for pesticide-induced DNA damage in North-West Indian agricultural workers.

Mechanism of Astragali Radix-Curcumae Rhizoma in treating gastric cancer based on network pharmacology and experimental verification

This study aims to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in the treatment of gastric cancer based on network pharmacology. Further, the SGC7901 cell model of gastric cancer was employed to validate the efficacy and key targets of the herb pair. Firstly, the CCK-8 assay was employed to evaluate the direct effect of HQEZ on the proliferation of gastric cancer SGC7901 cells. Then, network pharmacology methods were employed to investigate the active ingredients, key targets, and key signaling pathways involved in the treatment of gastric cancer with HQEZ. The results showed that HQEZ contained 18 potential active ingredients, such as quercetin, naringenin, and curcumin. The results of gene ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment suggested that the main targets of HQEZ in treating gastric cancer were involved in the regulation of protein serine/threonine kinase activity, activation of mitogen-activated protein kinase(MAPK) activity, cysteine-type endopeptidase activity, and negative regulation of protein serine/threonine kinase activity. The hypoxia-inducible factor-1(HIF-1) signaling pathway, ATP-binding cassette(ABC) transporters, cytochrome P450-mediated metabolism of xenobiotics, p53 signaling pathway, and cell apoptosis were key signaling pathways of HQEZ in treating gastric cancer. The cell experiments demonstrated that HQEZ significantly downregulated the expression of ATP-binding cassette subfamily B member 1(ABCB1), epidermal growth factor receptor(EGFR), phosphorylated serine/threonine kinase(p-AKT), hypoxia inducible factor 1 subunit alpha(HIF1A), B-cell lymphoma 2(BCL2), breast cancer susceptibility protein 1(BRCA1), DNA polymerase theta(POLH), ribonucleotide reductase M1(RRM1), and excision repair cross-complementation group 1(ERCC1), and upregulated the expression of tumor protein P53(TP53) and cysteinyl aspartate-specific proteinase(CAPS3). Finally, a multivariate COX regression model was adopted to study the relationship between gene expression and clinical information data of gastric cancer patients in the TCGA database, which demonstrated that the key targets of HQEZ were associated with the poor prognosis in gastric cancer patients. Further feature selection using the LASSO algorithm showed that EGFR, HIF1A, TP53, POLH, RRM1, and ERCC1 were closely associated with the survival of gastric can-cer patients. In conclusion, HQEZ regulates the expression of genes involved in DNA repair, survival, and apoptosis in gastric cancer cells via multiple targets and pathways, assisting the treatment of gastric cancer.

Characterizing excision repair cross-complementing family genes as drug resistance biomarkers in breast cancer

BackgroundExcision repair cross-complementing (ERCC) genes are important regulators of DNA repair processes, the aberrant expression of which may lead to treatment failures of breast cancer. The prognostic significance of the ERCC genes in several cancers has been investigated, except for breast cancer; therefore, we explored the ERCC genes, including ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, and ERCC8 in breast cancer, particularly during drug resistance processes.ResultsUsing the 2021 provisional study of The Metastatic Breast Cancer Project from cBioPortal, we identified ERCC genetic alterations in 8–36% of patients, where most alterations were considered amplifications followed by deep deletions. Pathway enrichment analyses identified Wnt signaling enrichment which contributed to cell proliferation. ERCC2 had the highest epigenetic alteration levels at 7 DNA methylation sites. Also, the mRNA levels of ERCC1, ERCC2, ERCC4, ERCC6, and ERCC8 were higher in patients with breast cancer when compared to normal breast tissues, with higher ERCC2 but lower ERCC8 levels in metastatic breast tissues. Breast cancer patients with low ERCC6 levels had better overall survival rates than the groups with higher ERCC6 levels. ERCC1, ERCC2, and ERCC4 were identified as endocrine therapy response predictors. ERCC1 was specifically an antihuman epidermal growth factor receptor therapy predictor, and ERCC1, ERCC2, ERCC6, and ERCC8 were chemotherapy response predictors.ConclusionWe used bioinformatics to investigate and identify the roles of ERCC genes in breast cancer resistant cells, in particular ERCC1, ERCC2, and ERCC6. We also showed how the Wnt pathway and DNA repair processes had a role in drug resistance in breast cancer cells, but further studies are required to validate those results.

Association of ERCC family mutations with prognosis and immune checkpoint inhibitors response in multiple cancers

The proteins encoded by the excision repair cross-complementing (ERCC) family are pivotal in DNA damage repair and maintaining genome stability. However, the precise role of the ERCC family in tumor prognosis and the effectiveness of immune checkpoint inhibitors (ICI) therapy remain uncertain. This study aimed to explore the connection between ERCC mutations and prognosis as well as the response to ICI. We observed that patients with ERCC mutations exhibited enhanced progression-free survival (PFS) and overall survival (OS) in two independent pan-cancer cohorts. Furthermore, this mutant subgroup showed higher tumor mutation burden (TMB) compared to the wild-type subgroup. Notably, ERCC mutations were associated with better OS (HR 0.54, 95% CI 0.42–0.70; P < 0.001) in pan-cancer patients who underwent ICI therapy (N = 1661). These findings were validated in a separate cohort, where patients in the ERCC mutant subgroup demonstrated improved clinical outcomes (HR 0.56, 95% CI 0.37–0.84; P = 0.03) and higher response rates (51.9% vs. 26.8%) than the wild-type subgroup. Further analysis revealed that patients with ERCC mutations displayed elevated tumor neoantigen burden (TNB) levels and increased infiltration of immune-response cells. Our study suggests that ERCC mutations are linked to enhanced immunogenicity and improved ICI efficacy, thus potentially serving as a biomarker for ICI therapy.

The Relationship between Single Nucleotide Polymorphism of ERCC1 Gene and the Response to Platinum Based Chemotherapy in Egyptian Non-Small Cell Lung Cancer Patients

Abstract Background Lung cancer (LC) is the second most common cancer diagnosed in both males and females. There are two subtypes of LC. Non-small cell lung cancer (NSCLC) is the major one. Treatment options for NSCLC depends mainly on the stage at diagnosis. The majority of the patients are diagnosed at advanced stages at time of presentation. Therefore, chemotherapy and radiotherapy play the dominant role in treatment of advanced NSCLC. The most commonly used chemotherapy is platinum-based chemotherapy as cisplatin and carboplatin and third generation drugs as vinorelbine and gemcitabine. The efficacy of platinum-based chemotherapy is limited by chemoresistance. The excision repair cross complementation group 1(ERCC1) gene is a member of nucleotide excision repair pathway that plays a critical role in the DNA repair by removing DNA covalent helix-distorting adducts. Aim of the Work In this study investigated the relationship between single nucleotide polymorphism of ERCC1 rs11615 and the response to platinum-based chemotherapy in Egyptian NSCLC patients in order to prevent the non-necessary exposure to the toxic effect of chemotherapy. Patients and Methods This is a cross-sectional study conducted on 50 NSCLC patients who were recruited from the Oncology Clinic in Ain Shams University Hospitals; twenty of them were responders to platinumbased chemotherapy and the other 30 were non-responders according to RECIST criteria. All subjects underwent full medical history focusing on tobacco smoking and family history of cancers, thorough clinical examination, histological diagnosis of NSCLC and TNM classification, radiological studies: computed tomography of chest and abdomen and laboratory investigations in the form of: complete blood picture (CBC), liver function tests and kidney function tests. Detection of the ERCC1 (T/C) polymorphism by realtime PCR was done for both the responders' and the non-responders' groups. Results There was no significant statistical difference observed between the responders’ and nonresponders’ groups regarding the genotype frequencies nor the allelic frequency (p &amp;gt; 0.05). Conclusion The present study did not confirm the presence of significant association between the genotypic frequencies nor the allelic frequencies of the ERCC1 rs 11615 among the responders' and the non-responders' groups. Further studies with higher sample size are needed to clarify the association.

Codelivery of ERCC2 small interfering RNA and cisplatin with macrophage-derived mimetic nanovesicles for enhanced bladder cancer treatment.

Cisplatin-based chemotherapy plays a vital role in the management of muscle-invasive bladder cancer (MIBC); however, off-tumor toxicity and resistance often lead to cancer recurrence and eventual treatment failure. The loss of function of the nucleotide excision repair gene excision repair cross-complementing rodent repair deficiency gene 2 ( ERCC2 ) in cancer cells correlates with sensitivity to cisplatin, while its overexpression causes cisplatin resistance. Small interfering RNA (siRNA) knockdown of ERCC2 combined with cisplatin treatment may improve therapeutic outcomes in patients with bladder cancer. Here, we aimed to develop macrophage-derived mimetic nanovesicles (MNVs) as a nanoplatform for the simultaneous delivery of cisplatin and ERCC2 siRNA for enhancing the efficacy of bladder cancer chemotherapy. The cellular uptake, gene down-regulation, tumor inhibition effects, and biosafety of the synthesized nanodrugs (MNV-Co) as a synergistic therapeutic strategy for MIBC were evaluated in vitro and in vivo . The results indicated high efficacy of MNV-Co against MIBC and low off-tumor toxicity. Furthermore, by down-regulating ERCC2 mRNA and protein levels, MNV-Co improved chemosensitivity, promoted cancer cell apoptosis, and effectively suppressed tumor growth. This study presents a potential approach for delivering cisplatin and ERCC2 siRNA concurrently to treat bladder cancer using a biomimetic nanosystem.

Effect of ERCC1 polymorphisms on the response to platinum-based chemotherapy: A systematic review and meta-analysis based on Asian population.

Platinum-based chemotherapy is one of the most common treatments for many cancers; however, the effect of chemotherapy varies from individual to individual. Excision repair cross complementation group 1 (ERCC1) is widely recognized as a key gene regulating nucleotide excision repair (NER) and is closely associated with platinum response. Many studies have yielded conflicting results regarding whether ERCC1 polymorphisms can affect the response to platinum and overall survival (OS). Therefore, it is necessary to perform a meta-analysis of patients with specific races and cancer types. Eight databases (EMBASE, PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, Scopus, VIP, China Biology Medicine disc and Wanfang databases) were searched. Results were expressed in terms of odds ratios (ORs), hazard ratios (HRs) and 95% CIs. In this study, rs11615, rs2298881 and rs3212986 SNPs were studied. In the comparison between CT and TT on the response to platinum, esophageal cancer [I2 = 0%, OR = 6.18, 95% CI(1.89,20.23), P = 0.003] and ovarian cancer [I2 = 0%, OR = 4.94, 95% CI(2.21,11.04), P<0.001] showed that the rs11615 CT genotype predicted a better response. In the comparison between CC and TT, ovarian cancer [I2 = 48.0%, OR = 6.15, 95% CI (2.56,14.29), P<0.001] indicated that the CC genotype predicted a better response. In the meta-analysis of OS, the CC genotype was related to longer OS than TT in ovarian cancer [TT vs CC: I2 = 57.7%, HR = 1.71, 95% CI (1.18, 2.49), P<0.001]. The ERCC1 rs11615 polymorphism was related to the response to platinum and OS, but the correlation is based on specific cancer types in the Asian population.

The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia

AbstractBiallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). The subjects presented with 19 different variants of ERCC6L2, and we identified a founder mutation, c.1424delT, in Finnish patients. The median age of the subjects at baseline was 18 years (range, 2-65 years). Changes in the complete blood count were mild despite severe bone marrow (BM) hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without HMs. Signs of progressive disease included increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in the BM morphology. The median age at the onset of HM was 37.0 years (95% CI, 31.5-42.5; range, 12-65 years). The overall survival (OS) at 3 years was 95% (95% CI, 85-100) and 19% (95% CI, 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome with a 3-year OS of 28% (95% CI, 0-61). Our results demonstrated the importance of early recognition and active surveillance in patients with biallelic germ line ERCC6L2 variants.

Association of ERCC1 and XPF polymorphisms with pediatric glioma susceptibility.

Association of ERCC1 and XPF polymorphisms with pediatric glioma susceptibility.

DNA repair in cardiomyocytes is critical for maintaining cardiac function in mice.

Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.

ERCC6L facilitates the progression of laryngeal squamous cell carcinoma by the binding of FOXM1 and KIF4A

The role of excision repair cross-complementation group 6-like (ERCC6L) has been reported in several cancers, but little is known about its expression and function in laryngeal squamous cell carcinoma (LSCC). In this study, the expression of ERCC6L in LSCC was determined by immunohistochemistry and its correlation with prognostic factors was analyzed. Furthermore, cytological functional validation elucidated the role and underlying mechanisms of ERCC6L dysregulation in LSCC. Our data revealed that ERCC6L expression was elevated in LSCC and it’s correlated with TNM stage. In addition, ERCC6L knockdown LSCC cells showed decreased proliferation and migration, increased apoptosis, and reactive oxygen species (ROS). Mechanically, overexpression of ERCC6L promoted nuclear translocation of FOXM1 to facilitate direct binding to the KIF4A promoter and upregulated KIF4A expression. Furthermore, KIF4A knockdown attenuated the role of ERCC6L overexpression in promoting proliferation, migration, and tumorigenesis of LSCC cells. In summary, ERCC6L promoted the binding of FOXM1 and KIF4A in LSCC cells to drive their progression, which may be a promising target for precision therapy in this disease.

Perspectives of ERCC1 in early-stage and advanced cervical cancer: From experiments to clinical applications.

Cervical cancer is a public health problem of extensive clinical importance. Excision repair cross-complementation group 1 (ERCC1) was found to be a promising biomarker of cervical cancer over the years. At present, there is no relevant review article that summarizes such evidence. In this review, nineteen eligible studies were included for evaluation and data extraction. Based on the data from clinical and experimental studies, ERCC1 plays a key role in the progression of carcinoma of the uterine cervix and the therapeutic response of chemoradiotherapy. The majority of the included studies (13/19, 68%) suggested that ERCC1 played a pro-oncogenic role in both early-stage and advanced cervical cancer. High expression of ERCC1 was found to be associated with the poor survival rates of the patients. ERCC1 polymorphism analyses demonstrated that ERCC1 might be a useful tool for predicting the risk of cervical cancer and the treatment-related toxicities. Experimental studies indicated that the biological effects exerted by ERCC1 in cervical cancer might be mediated by its associated genes and affected signaling pathways (i.e., XPF, TUBB3, and. To move towards clinical applications by targeting ERCC1 in cervical cancer, more clinical, in-vitro, and in-vivo investigations are still warranted in the future.