Dual­regulated oncolytic adenovirus carrying ERCC1­siRNA gene possesses potent antitumor effect on ovarian cancer cells.

Ovarian cancer is a multifactorial and deadly disease. Despite significant advancements in ovarian cancer therapy, its incidence is on the rise and the molecular mechanisms underlying ovarian cancer invasiveness, metastasis and drug resistance remain largely elusive, resulting in poor prognosis. Oncolytic viruses armed with therapeutic transgenes of interest offer an attractive alternative to chemical drugs, which often face innate and acquired drug resistance. The present study constructed a novel oncolytic adenovirus carrying ERCC1 short interfering (si)RNA, regulated by hTERT and HIF promoters, termed Ad­siERCC1. The findings demonstrated that this oncolytic adenovirus effectively inhibits the proliferation, migration and invasion of ovarian cancer cells. Furthermore, the downregulation of ERCC1 expression by siRNA ameliorates drug resistance to cisplatin (DDP) chemotherapy. It was found that Ad­siERCC1 blocks the cell cycle in the G1 phase and enhances apoptosis through the PI3K/AKT­caspase­3 signaling pathways in SKOV3 cells. The results of the present study highlighted the critical effect of oncolytic virus Ad­siERCC1 in inhibiting the survival of ovarian cancer cells and increasing chemotherapy sensitivity to DDP. These findings underscore the potent antitumor effect of Ad­siERCC1 on ovarian cancers in vivo.

Gene expression markers in peripheral blood and outcome in patients with platinum-resistant ovarian cancer: A study of the European GANNET53 consortium.

Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.

Relationship between ERCC1 and XPC polymorphisms and the susceptibility to head and neck carcinoma: A systematic review, meta-analysis, and trial sequential analysis.

OBJECTIVE: This meta-analysis was conducted to investigate the relationship between ERCC1 and XPC polymorphisms and the risk of head and neck cancer (HNC), incorporating more studies and additional analyses. DESIGN: An exhaustive search of various databases, including PubMed/Medline, Web of Science, Scopus, and Cochrane Library was carried out, up until November 18, 2023, to identify pertinent studies. The Review Manager 5.3 software was employed to calculate the effect sizes, which were presented as the odds ratio (OR) along with a 95% confidence interval (CI). RESULTS: The study found that the T allele (OR = 1.11; p-value = 0.02; 95%CI: 1.02, 1.22) and the TT genotype rs2228000 polymorphism in both the homozygous model (OR = 1.61, p-value = 0.02; 95%CI: 1.07, 2.42) and the recessive model (OR = 1.53; p-value = 0.02; 95%CI: 1.06, 2.22) had statistically significant associations. However, no significant associations were found for rs11615, rs3212986, rs735482, rs2228001, and PAT polymorphisms in any genetic models. CONCLUSIONS: The meta-analysis revealed significant associations for the T allele and TT genotype rs2228000 polymorphism, but not for rs11615, rs3212986, rs735482, rs2228001, and PAT polymorphisms. The results highlight the impact of factors such as ethnicity, cancer subtype, and control source on these associations, emphasizing the intricate nature of genetic interactions in disease risk.

Podocyte Ercc1 is indispensable for glomerular integrity.

As life expectancy continues to increase, age-related kidney diseases are becoming more prevalent. Chronic kidney disease (CKD) is not only a consequence of aging but also a potential accelerator of aging process. Here we report the pivotal role of podocyte ERCC1, a DNA repair factor, in maintaining glomerular integrity and a potential effect on multiple organs. Podocyte-specific ERCC1-knockout mice developed severe proteinuria, glomerulosclerosis, and renal failure, accompanied by a significant increase in glomerular DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). ERCC1 gene transfer experiment in the knockout mice attenuated proteinuria and glomerulosclerosis with reduced DNA damage. Notably, CD44+CD8+ memory T cells, indicative of T-cell senescence, were already elevated in the peripheral blood of knockout mice at 10 weeks old. Additionally, levels of senescence-associated secretory phenotype (SASP) factors were significantly increased in both the circulation and multiple organs of the knockout mice. In older mice and human patients, we observed an accumulation of DSBs and an even greater buildup of SSBs in glomeruli, despite no significant reduction in ERCC1 expression with age in mice. Collectively, our findings highlight the crucial role of ERCC1 in repairing podocyte DNA damage, with potential implications for inflammation in various organs.

Hybrid Molecular and Functional Micro-CT Imaging Reveals Increased Myocardial Apoptosis Preceding Cardiac Failure in Progeroid Ercc1 Mice.

PURPOSE: In this study, we explored the role of apoptosis as a potential biomarker for cardiac failure using functional micro-CT and fluorescence molecular tomography (FMT) imaging techniques in Ercc1 mutant mice. Ercc1 is involved in multiple DNA repair pathways, and its mutations contribute to accelerated aging phenotypes in both humans and mice, due to the accumulation of DNA lesions that impair vital DNA functions. We previously found that systemic mutations and cardiomyocyte-restricted deletion of Ercc1 in mice results in left ventricular (LV) dysfunction at older age. PROCEDURES AND RESULTS: Here we report that combined functional micro-CT and FMT imaging allowed us to detect apoptosis in systemic Ercc1 mutant mice prior to the development of overt LV dysfunction, suggesting its potential as an early indicator and contributing factor of cardiac impairment. The detection of apoptosis in vivo was feasible as early as 12 weeks of age, even when global LV function appeared normal, underscoring the potential of apoptosis as an early predictor of LV dysfunction, which subsequently manifested at 24 weeks. CONCLUSIONS: This study highlights the utility of combined functional micro-CT and FMT imaging in assessing cardiac function and detecting apoptosis, providing valuable insights into the potential of apoptosis as an early biomarker for cardiac failure.

Ercc1 DNA repair deficiency results in vascular aging characterized by VSMC phenotype switching, ECM remodeling, and an increased stress response.

Cardiovascular diseases are the number one cause of death globally. The most important determinant of cardiovascular health is a person's age. Aging results in structural changes and functional decline of the cardiovascular system. DNA damage is an important contributor to the aging process, and mice with a DNA repair defect caused by Ercc1 deficiency display hypertension, vascular stiffening, and loss of vasomotor control. To determine the underlying cause, we compared important hallmarks of vascular aging in aortas of both Ercc1Δ/- and age-matched wildtype mice. Additionally, we investigated vascular aging in 104 week old wildtype mice. Ercc1Δ/- aortas displayed arterial thickening, a loss of cells, and a discontinuous endothelial layer. Aortas of 24 week old Ercc1Δ/- mice showed phenotypical switching of vascular smooth muscle cells (VSMCs), characterized by a decrease in contractile markers and a decrease in synthetic markers at the RNA level. As well as an increase in osteogenic markers, microcalcification, and an increase in markers for damage induced stress response. This suggests that Ercc1Δ/- VSMCs undergo a stress-induced contractile-to-osteogenic phenotype switch. Ercc1Δ/- aortas showed increased MMP activity, elastin fragmentation, and proteoglycan deposition, characteristic of vascular aging and indicative of age-related extracellular matrix remodeling. The 104 week old WT mice showed loss of cells, VSMC dedifferentiation, and senescence. In conclusion, Ercc1Δ/- aortas rapidly display many characteristics of vascular aging, and thus the Ercc1Δ/- mouse is an excellent model to evaluate drugs that prevent vascular aging in a short time span at the functional, histological, and cellular level.

Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein-Protein Interaction.

The DNA excision repair protein ERCC1 and the DNA damage sensor protein, XPA are highly overexpressed in patient samples of cisplatin-resistant solid tumors including lung, bladder, ovarian, and testicular cancer. The repair of cisplatin-DNA crosslinks is dependent upon nucleotide excision repair (NER) that is modulated by protein-protein binding interactions of ERCC1, the endonuclease, XPF, and XPA. Thus, inhibition of their function is a potential therapeutic strategy for the selective sensitization of tumors to DNA-damaging platinum-based cancer therapy. Here, we report on new small-molecule antagonists of the ERCC1/XPA protein-protein interaction (PPI) discovered using a high-throughput competitive fluorescence polarization binding assay. We discovered a unique structural class of thiopyridine-3-carbonitrile PPI antagonists that block a truncated XPA polypeptide from binding to ERCC1. Preliminary hit-to-lead studies from compound 1 reveal structure-activity relationships (SAR) and identify lead compound 27 o with an EC50 of 4.7 µM. Furthermore, chemical shift perturbation mapping by NMR confirms that 1 binds within the same site as the truncated XPA67-80 peptide. These novel ERCC1 antagonists are useful chemical biology tools for investigating DNA damage repair pathways and provide a good starting point for medicinal chemistry optimization as therapeutics for sensitizing tumors to DNA damaging agents and overcoming resistance to platinum-based chemotherapy.

Unveiling Novel ERCC1-XPF Complex Inhibitors: Bridging the Gap from In Silico Exploration to Experimental Design.

Modifications in DNA repair pathways are recognized as prognostic markers and potential therapeutic targets in various cancers, including non-small cell lung cancer (NSCLC). Overexpression of ERCC1 correlates with poorer prognosis and response to platinum-based chemotherapy. As a result, there is a pressing need to discover new inhibitors of the ERCC1-XPF complex that can potentiate the efficacy of cisplatin in NSCLC. In this study, we developed a structure-based virtual screening strategy targeting the inhibition of ERCC1 and XPF interaction. Analysis of crystal structures and a library of small molecules known to act against the complex highlighted the pivotal role of Phe293 (ERCC1) in maintaining complex stability. This residue was chosen as the primary binding site for virtual screening. Using an optimized docking protocol, we screened compounds from various databases, ultimately identifying more than one hundred potential inhibitors. Their capability to amplify cisplatin-induced cytotoxicity was assessed in NSCLC H1299 cells, which exhibited the highest ERCC1 expression of all the cell lines tested. Of these, 22 compounds emerged as promising enhancers of cisplatin efficacy. Our results underscore the value of pinpointing crucial molecular characteristics in the pursuit of novel modulators of the ERCC1-XPF interaction, which could be combined with cisplatin to treat NSCLC more effectively.

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

BACKGROUND: Occupational 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. METHODS: This 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. RESULTS: Our 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). CONCLUSION: ERCC1, 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.

Genotyping, in silico screening and molecular dynamics simulation of SNPs of MGMT and ERCC1 gene in lung cancer patients treated with platinum-based doublet chemotherapy.

Lung cancer, the leading cause of death worldwide, arises from an intricate combination of genetic and environmental factors. Genetic variations can influence the chemotherapeutic response of lung cancer patients in DNA repair genes. This study examines the response to platinum-based drugs among lung cancer patients of North Indian descent who possess genetic variations in the MGMT and ERCC1 genes. P CR-RFLP method was used for genotypic analysis. MedCalc statistical software was used to calculate odds ratios and Median Survival Time (MST). GROMACS software was used to perform Molecular dynamic simulation. ADCC Patients revealed a significant association with MGMT in the heterozygous genotype (HR= 1.56, p=0.02) and also with ERCC1 in both mutant and combined variants (HR= 1.25, p=0.01; HR=0.78, p=0.03). SQCC subjects harbouring ERCC1 polymorphism also reported a 2-fold increase in hazard ratio and a corresponding decrease in survival time for heterozygous and combined variants (HR= 2.55, p=0.02; HR 2.33, p=0.01, respectively). MD simulation results demonstrate a lower RMSD, stable radius of gyration, and lower RMSF, indicating the mutated MGMT protein is more stable than the wild. Further, the docking score for DNA-Wild and DNA-L84F mutants are -201.6 and -131.8, respectively. MD Simulation of the complexes further validated the results. Our study concludes that MGMT and ERCC1 polymorphisms are associated with decreased overall survival. Further, computational analysis of MGMT (rs12917) polymorphism revealed that mutated MGMT cannot bind properly to the DNA and hence cannot properly repair DNA, resulting in lower overall survival.Communicated by Ramaswamy H. Sarma.

Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine.

Base excision repair (BER) corrects forms of oxidative, deamination, alkylation, and abasic single-base damage that appear to have minimal effects on the helix. Since its discovery in 1974, the field has grown in several facets: mechanisms, biology and physiology, understanding deficiencies and human disease, and using BER genes as potential inhibitory targets to develop therapeutics. Within its segregation of short nucleotide (SN-) and long patch (LP-), there are currently six known global mechanisms, with emerging work in transcription- and replication-associated BER. Knockouts (KOs) of BER genes in mouse models showed that single glycosylase knockout had minimal phenotypic impact, but the effects were clearly seen in double knockouts. However, KOs of downstream enzymes showed critical impact on the health and survival of mice. BER gene deficiency contributes to cancer, inflammation, aging, and neurodegenerative disorders. Medicinal targets are being developed for single or combinatorial therapies, but only PARP and APE1 have yet to reach the clinical stage.

ERCC1 and MGMT Methylation as a Predictive Marker of Relapse and FOLFOX Response in Colorectal Cancer Patients from South Tunisia.

Genetic and epigenetic modifications present a major cause of relapse and treatment failure in colorectal cancer. This study aims to appreciate the prognostic and predictive value of ERRC1 and MGMT methylation. We also studied the prognostic impact of the ERCC1 rs11615 polymorphism as well as its expression. Methylation profiles of ERCC1 and MGMT were tested by methylation-specific PCR. A polymorphism of ERCC1 was studied using PCR-RFLP and its expression was examined by immunohistochemistry. ERCC1 was methylated in 44.6% of colorectal adenocarcinoma while MGMT was methylated in 69% of cases. MGMT methylation was strongly associated with lymph node metastasis, lymph invasion, venous invasion, perineural invasion, distant metastasis and relapse. Patients with methylation of both genes were more likely to have a poor prognosis and display chemoresistance. IHC analysis revealed that ERCC1 staining was noted in 52.8% of colorectal adenocarcinoma and inversely related to distant metastasis and cancer recurrence. Kaplan Meier analysis revealed that the worst overall survival was significantly associated with ERCC1 and MGMT methylation while decreased ERCC1 expression and T/T genotype exhibited the best overall survival. The methylation of MGMT, alone or combined with ERCC1, is predictive for poor prognosis, short overall survival and chemotherapy response in colorectal cancer.

Cangfu Daotan Wan alleviates polycystic ovary syndrome with phlegm-dampness syndrome via disruption of the PKP3/ERCC1/MAPK axis.

BACKGROUND/AIM: Cangfu Daotan Wan (CFDTW) has been widely used for polycystic ovary syndrome (PCOS) patients in the type of stagnation of phlegm and dampness. In this study, we aimed to evaluate the mechanism underlying the therapeutic effect of CFDTW on PCOS with phlegm-dampness syndrome (PDS). METHODS: In silico analysis was adopted to identify CFDTW potential targets and the downstream pathways in the treatment of PCOS. Expression of PKP3 was examined in the ovarian granulosa cells from PCOS patients with PDS and rat PCOS models induced by dehydroepiandrosterone (DHEA). PKP3/ERCC1 was overexpressed or underexpressed or combined with CFDTW treatment in ovarian granulosa cells to assay the effect of CFDTW on ovarian granulosa cell functions via the PKP3/MAPK/ERCC1 axis. RESULTS: Clinical samples and ovarian granulosa cells of rat models were characterized by hypomethylated PKP3 promoter and upregulated PKP3 expression. CFDTW reduced PKP3 expression by enhancing the methylation of PKP3 promoter, leading to proliferation of ovarian granulosa cells, increasing S and G2/M phase-arrested cells, and arresting their apoptosis. PKP3 augmented ERCC1 expression by activating the MAPK pathway. In addition, CFDTW facilitated the proliferation of ovarian granulosa cells and repressed their apoptosis by regulating PKP3/MAPK/ERCC1 axis. CONCLUSION: Taken together, this study illuminates how CFDTW confers therapeutic effects on PCOS patients with PDS, which may offer a novel theranostic marker in PCOS.

XPF-ERCC1 Blocker Improves the Therapeutic Efficacy of 5-FU- and Oxaliplatin-Based Chemoradiotherapy in Colorectal Cancer.

5-FU-based chemoradiotherapy (CRT) and oxaliplatin-based CRT are commonly used therapies for advanced colorectal cancer (CRC). However, patients with a high expression of ERCC1 have a worse prognosis than those with a low expression. In this study, we investigated the effect of XPF-ERCC1 blockers on chemotherapy and 5-FU-based CRT and oxaliplatin (OXA)-based CRT in colorectal cancer cell lines. We investigated the half-maximal inhibitory concentration (IC50) of 5-FU, OXA, XPF-ERCC1 blocker, and XPF-ERCC1 blocker, and 5-FU or OXA combined and analyzed the effect of XPF-ERCC1 blocker on 5-FU-based CRT and oxaliplatin-based CRT. Furthermore, the expression of XPF and γ-H2AX in colorectal cells was analyzed. In animal models, we combined the XPF-ERCC1 blocker with 5-FU and OXA to investigate the effects of RC and finally combined the XPF-ERCC1 blocker with 5-FU- and oxaliplatin-based CRT. In the IC50 analysis of each compound, the cytotoxicity of the XPF-ERCC1 blocker was lower than that of 5-FU and OXA. In addition, the XPF-ERCC1 blocker combined with 5-FU or OXA enhanced the cytotoxicity of the chemotherapy drugs in colorectal cells. Furthermore, the XPF-ERCC1 blocker also increased the cytotoxicity of 5-FU-based CRT and OXA -based CRT by inhibiting the XPF product DNA locus. In vivo, the XPF-ERCC1 blocker was confirmed to enhance the therapeutic efficacy of 5-FU, OXA, 5-FU-based CRT, and OXA CRT. These findings show that XPF-ERCC1 blockers not only increase the toxicity of chemotherapy drugs but also increase the efficacy of combined chemoradiotherapy. In the future, the XPF-ERCC1 blocker may be used to improve the efficacy of 5-FU- and oxaliplatin-based CRT.

HPV virus and biomarkers of resistance to chemoradiation in circulating tumor cells from patients with squamous cell carcinoma of the anus.

Localized anal cancer is mostly represented by squamous cell carcinoma of the anus (SCCA) and is cured in ≥80 % of cases by chemoradiation (CRT). Development of techniques for detection/evaluating circulating tumor cells (CTCs) for diagnosis/ prognosis/response to therapy can change the manner we treat/follow SCCA patients. OBJECTIVE: to detect CTCs from patients with SCCA and evaluate the presence of HPV virus, p16 expression and markers related to resistance to CRT (RAD23B/ ERCC1/ TYMS) in CTCs at baseline and after CRT. METHODS: CTCs were isolated/quantified by ISET®, protein expressions were analyzed by immunocytochemistry and HPV DNA was detected by chromogenic in situ hybridization. RESULTS: We enrolled 15 patients: median age was 61 (43-73) years, the majority was women (10/15). CTCs were detected in all patients at baseline (median= 0.4 (0.4-3.33) CTCs/mL) and in 8/9 patients, after CRT (median= 2.33 (0-7.0) CTCs/mL). DNA from HPV was found in CTCs in 14/15 patients (93.33 %) at baseline and in 7/9 (77.7 %) after treatment. At a median follow-up of 22.20 (1.45-38.55) months, three patients expressed ERCC1 in CTCs after treatment, with one of them having disease recurrence. CONCLUSION: We showed that detection of HPV in CTCs from patients with non-metastatic SCCA is feasible and appears to be a sensitive diagnostic method. These results may be clinically useful for better monitoring these patients. However, future larger cohorts may demonstrate whether there is any correlation between the presence of HPV and the expression of screening markers for CRT in SCCA.

Genetic Polymorphisms in ERCC1 Gene and Their Association with Response to Radiotherapy in Moroccan Patients with Nasopharyngeal Carcinoma.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is a severe malignant disease. Despite its low frequency, NPC is very common in North African population. Radiotherapy is the standard therapeutic treatment of NPC. However, radioresistance hampers the success of treatment. At the molecular scale, radioresistance is due to genetic variations involved in DNA repair pathways in NPC patients. Several studies reported that single nucleotide polymorphisms (SNPs) in excision repair cross complementing group 1 (ERCC1) could be associated with radioresistance. In this optic, the present study aimed to evaluate the association between DNA repair gene polymorphisms ERCC1 C8092A and ERCC1 C118T and radiotherapy response of patients with NPC. METHODS: A total of 95 patients with confirmed NPC were recruited at the Mohammed VI Center for Cancer Treatment, Casablanca - Morocco between 2016 and 2018. Two single nucleotide polymorphisms in ERCC1 gene were genotyped. Multiple analysis software was used to assess the correlation between these SNPs and radio-therapeutic response. RESULTS: Sequencing of ERCC1 C8092A polymorphism revealed that CC and CA genotypes were found in 51.6% and 45.3% of cases, respectively, whereas the homozygote AA genotype was reported in only 3.1% of cases. For ERCC1 C118T polymorphism, the heterozygote CT genotype was identified in 49.5% of cases. Homozygotes genotypes CC and TT were detected in 17.9% and 32.6% respectively of NPC cases. Of note, no significant association was found between the ERCC1 C8092A polymorphism and response to radiation therapy (p=0.81). Similarly, there was no significant association between the response to radiotherapy and allelic distribution (p=0.56). Likewise, no correlation was observed neither with genotypes (p=0.07) nor with alleles (p=0.09) of ERCC1 C118T polymorphism and response to radiation therapy. CONCLUSION: Our results clearly showed that ERCC1 C8092A and ERCC1 C118T polymorphisms were not associated with response to radiotherapy in Moroccan NPC patients. Large studies are warranted to confirm the role of these SNPs in therapeutic response of NPC patients.

The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy.

BACKGROUND: A rare yet severe neoplasia called malignant pleural mesothelioma (MPM) typically manifests itself in advanced stages. Despite some improvements in the treatment of patients with MPM, this malignancy continues to have a detrimental prognosis . The primary goal of the present study was to assess the associatin between ERCC1, RRM1, and thymidylate synthase (TS) expression and disease outcome in patients with malignant pleural mesothelioma (MPM) treated with either pemetrexed plus cisplatin or gemcitabine plus cisplatin. METHODS: This prospective cohort study was done on ninety-one advanced MPM patients. The patients received either pemetrexed plus platinum (55 of 91) or gemcitabine plus platinum chemotherapy (36 of 91). Tissue biopsy was taken at time of diagnosis. Immunohistochemistry was used to assess the levels of ERCC1, RRM1, and TS transcription in tissue biopsies (paraffin embedded). RESULTS: Based on the findings, 70% of patients with low expression of TS had low expression of ERCC1, and 68% of patients with high expression of TS had high expression of ERCC1, suggesting  a significat association between ERCC1 expression and TS expression (p=0.005). However, there was no relation between ERCC1 and RRM1 expression patterns (p= 0.296). In patients underwen platinum-based theraphy (n 91), a significant correlation was detected between low ERCC1 median High-scoring and longer progression time (TTP;9.6 v 5.3 months;P< .001) or overall survival (OS) (OS;18.1 v 9.1 months; P<0.001). A significant correlation was found between low TS protein expression and longer time progression (TTP; 11.8 v 5.4 months; P< .001) or OS (OS; 19.8 v 8.5 months; P <0.001) in patients undergoing pemetrexed plus platinum chemotherapy (n 55). Low RRM1 expression was accompanied by high progression free survival (TTP; 10.6 v 3.8 months) and OS (OS; 20.6 v 8.6 months) in patients receiving gemcitabine plus platinum chemotherapy. Based on the multivariate test results, the independent variables significantly affecting OS were tumor stage (HR: 2.3; 95% CI: 1.1-4.9; p= 0.021) and ERCC1 (HR: 2.7; 95% CI: 1.7-4.3; p < 0.001). CONCLUSION: Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.

Involvement of ERCC1 (rs3212986) and ERCC2 (rs1799793, rs13181) polymorphisms of DNA repair genes in breast cancer occurrence in Burkina Faso.

BACKGROUND: Genetic alterations can result in DNA repair defects, increasing susceptibility to breast cancer. The aim of this study was to evaluate the involvement of two DNA repair genes, ERCC1 (rs3212986, GenBank NC_000073.9) and ERCC2 (rs1799793, rs13181, GenBank: NC_000019.10) in the occurrence of breast cancer in Burkina Faso. METHODS: This case-control study enrolled 128 participants including 64 patients and 64 healthy controls. Genotyping of polymorphisms were performed by real-time PCR and PCR-RFLP. RESULTS: The heterozygous AC genotype of the ERCC2rs13181 polymorphism was associated with the occurrence of breast cancer when the mutant allele is inherited under the dominant pattern (CC/AC vs AA; OR = 2.74, 95% IC (1.09-6.87); p = .028), but this association became insignificant after the Bonferroni correction (p = .156). No association was observed between ERCC1rs3212986 and ERCC2rs1799793 polymorphisms and breast cancer risk. CONCLUSION: This study showed that the heterozygous genotype (CA) of the ERCC2rs13181 polymorphism may be associated with a risk of breast cancer.

Breast cancer pharmacogenetics: a systematic review.

Breast cancer was declared the most prevalent type of cancer in 2020. Among other factors, treatment response can be affected by genetic polymorphisms - which is the focus of pharmacogenetics - and ethnicity is also a contributing factor in this context. Relevant genes in disease treatment pathways were selected to evaluate treatment response from the pharmacogenetic perspective; polymorphism frequencies and ethnic and continental representation across the available literature were also assessed through a systematic review. The identified associations and gaps have been described in this study with the purpose that, in the future, treatments can be personalized and thus be more effective, safer, and accessible to all.