Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

UNASSIGNED: Trichothiodystrophy-1 (TTD1) is an autosomal-recessive disease and caused by mutations in ERCC2, a gene coding for a subunit of the TFIIH transcription and nucleotide-excision repair (NER) factor. In almost half of these patients infectious susceptibility has been reported but the underlying molecular mechanism leading to immunodeficiency is largely unknown.
UNASSIGNED: The aim of this study was to perform extended molecular and immunological phenotyping in patients suffering from TTD1.
UNASSIGNED: Cellular immune phenotype was investigated using multicolor flow cytometry. DNA repair efficiency was evaluated in UV-irradiation assays. Furthermore, early BCR activation events and proliferation of TTD1 lymphocytes following DNA damage induction was tested. In addition, we performed differential gene expression analysis in peripheral lymphocytes of TTD1 patients.
UNASSIGNED: We investigated three unrelated TTD1 patients who presented with recurrent infections early in life of whom two harbored novel ERCC2 mutations and the third patient is a carrier of previously described pathogenic ERCC2 mutations. Hypogammaglobulinemia and decreased antibody responses following vaccination were found. TTD1 B-cells showed accumulation of γ-H2AX levels, decreased proliferation activity and reduced cell viability following UV-irradiation. mRNA sequencing analysis revealed significantly downregulated genes needed for B-cell development and activation. Analysis of B-cell subpopulations showed low numbers of naïve and transitional B-cells in TTD1 patients, indicating abnormal B-cell differentiation in vivo.
UNASSIGNED: In summary, our analyses confirmed the pathogenicity of novel ERCC2 mutations and show that ERCC2 deficiency is associated with antibody deficiency most likely due to altered B-cell differentiation resulting from impaired BCR-mediated B-cell activation and activation-induced gene transcription.

Introduction: One of the primary obstacles faced by individuals with advanced colorectal cancer (CRC) is the potential development of acquired chemoresistance as the disease advances. Studies have indicated a direct association between elevated levels of miR-92a-3p and the progression, metastasis, and chemoresistance observed in CRC. We proposed that miR-92a-3p impairs FOLFOX (fluorouracil/oxaliplatin) chemotherapy response by upregulating the expression of chemoresistance biomarker genes through the activation of β-catenin and epithelial-mesenchymal transition (EMT). These FOLFOX biomarker genes include the pyrimidine biosynthesis pathway genes dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and the genes encoding the DNA repair complexes subunits ERCC1 and ERCC2, and XRCC1. Methods: To assess this, we transfected SW480 and SW620 colon cancer cell lines with miR-92a-3p mimics and then quantified the expression of DPYD, TYMS, MTHFR, ERCC1, ERCC2, and XRCC1, the expression of EMT markers and transcription factors, and activation of β-catenin. Results and discussion: Our results reveal that miR-92a-3p does not affect the expression of DPYD, TYMS, MTHFR, and ERCC1. Furthermore, even though miR-92a-3p affects ERCC2, XRCC1, E-cadherin, and β-catenin mRNA levels, it has no influence on their protein expression. Conclusion: We found that miR-92a-3p does not upregulate the expression of proteins of DNA-repair pathways and other genes involved in FOLFOX chemotherapy resistance.

ERCC2 plays a pivotal role in DNA damage repair, however, its specific function in cancer remains elusive. In this study, we made a significant breakthrough by discovering a substantial upregulation of ERCC2 expression in glioblastoma (GBM) tumor tissue. Moreover, elevated levels of ERCC2 expression were closely associated with poor prognosis. Further investigation into the effects of ERCC2 on GBM revealed that suppressing its expression significantly inhibited malignant growth and migration of GBM cells, while overexpression of ERCC2 promoted tumor cell growth. Through mechanistic studies, we elucidated that inhibiting ERCC2 led to cell cycle arrest in the G0/G1 phase by blocking the CDK2/CDK4/CDK6/Cyclin D1/Cyclin D3 pathway. Notably, we also discovered a direct link between ERCC2 and CDK4, a critical protein in cell cycle regulation. Additionally, we explored the potential of TRAIL, a low-toxicity death ligand cytokine with anticancer properties. Despite the typical resistance of GBM cells to TRAIL, tumor cells undergoing cell cycle arrest exhibited significantly enhanced sensitivity to TRAIL. Therefore, we devised a combination strategy, employing TRAIL with the nanoparticle DMC-siERCC2, which effectively suppressed the GBM cell proliferation and induced apoptosis. In summary, our study suggests that targeting ERCC2 holds promise as a therapeutic approach to GBM treatment.

Glioma is the most common type of primary brain tumour which accounts for about 30% of all brain and central nervous system tumours, and approximately 70% of adult malignant brain tumours. Numerous studies have been performed to assess the relationship between ERCC2 rs13181 polymorphism and the risk of glioma development, yet these findings of these studies are often inconsistent and contradictory. Therefore, the aim of this study is to conduct a systematic review and meta-analysis to assess the role of ERCC2 rs13181 in glioma developing. In this work, we have conducted a systematic review and meta-analysis. In order to collect the results of relevant studies on the association of ERCC2 rs13181 gene polymorphism with glioma, we initially searched the Scopus, Embase, Web of Science (WoS), PubMed, and ScienceDirect databases, without a lower time limit, and until June 2020. In order to analyse the eligible studies, the random effects model was used and the heterogeneity of the studies was investigated with the I 2 index. Data analysis was performed within the Comprehensive Meta-Analysis software (version 2). The total number of studies that focused on patients with glioma was 10. The odds ratio of GG vs TT genotype in patients with glioma based on meta-analysis was 1.08 (0.85-1.37: 95% confidence interval), which indicates the increasing effect of GG vs TT genotype by 0.08. The odds ratio of GG + TG vs TT genotype in patients with glioma was 1.22 (1.38-1.7: 95% confidence interval) based on meta-analysis, which indicates the increasing effect of GG + TG vs TT genotype as 0.22. The odds ratio of TG vs TT genotype in patients with glioma was 1.2 (0.38-1.4: 95% confidence interval), which shows the increasing effect of TG vs TT genotype by 0.2. The odds ratio of G vs T genotype in patients with glioma based on the meta-analysis was 1.15 (1.26-1.4: 95% confidence interval), which indicates the increasing effect of G vs T genotype by 0.15. The odds ratio of GG vs TG + TT genotype in patients with glioma based on meta-analysis was 1.22 (1.33-1.45: 95% confidence interval), which indicates the increasing effect of GG vs TG + TT genotype by 0.22. The results of this systematic review and meta-analysis show that ERCC2 rs13181 polymorphism and its genotypes are an important risk factor for genetic susceptibility to glioma tumour.

Small cell bladder carcinoma (SCBC) represents a rare histologic variant with a poor prognosis and for which no routine biomarkers exist. Limited reports of genomic sequencing in SCBC have demonstrated a high prevalence of TP53 and RB1 gene mutations, though the prognostic value of these and other gene variants in SCBC remains undefined. In this study, we performed targeted genomic sequencing on a cohort of SCBC patients and correlated genomic findings with clinical outcomes to identify potential novel biomarkers.
Thirty-one patients with SCBC and available treatment-naïve tumor specimens were identified from an institutional database (23 limited stage [LS], 8 extensive stage [ES]). Small cell carcinoma specimens were microdissected and subjected to tumor next-generation whole-exon sequencing with a 592 gene panel. Kaplan-Meier techniques and Cox proportional hazards models were used to evaluate genomic aberration association with relapse-free survival (RFS) and overall survival (OS) in the limited stage cohort.
The most common pathogenic gene variants included ARID1A (48%), TP53 (48%) and RB1 (48%). Mutations in genes with potential therapeutic targets not routinely evaluated in SCBC included BRCA1/2 (16%), POLE (13%), JAK2 (13%), PDGFB (13%) and FGFR3 (3%). Multiple novel biomarker candidates showed trends for improvements in OS in the LS subset including ERCC2 (HR 0.322, P = 0.122) and RB1 (HR 0.481, P = 0.182), while LS patients with TP53 mutations (HR 2.730, P = 0.056), and MCL1 gene amplification (HR 4.183, P = 0.018) suggested inferior OS. Additionally, gene or copy number variants with potential prognostic benefit included UBR5 and DAXX (P = 0.02, [hazard ratios nonestimable due to zero events in biomarker positive groups]).
These results support the role for tumor genomic profiling in SCBC and identify multiple potential novel biomarkers and therapeutic targets in this rare disease. Efforts to validate these findings should lead to improved decision-making and treatment outcomes in SCBC.

BACKGROUND: Breast cancer (BC) is the most common disease in women and the leading cause of death from cancer globally. Epidemiological studies examined that nucleotide excision repair genes ERCC2 (rs13181) and ERCC4 (rs2276466) SNPs might increase cancer risk. Based on the previous investigation, this study was conducted to explore the correlation between these polymorphisms and BC susceptibility in Bangladeshi women.
RESULTS: Between January 2019 and January 2020, 140 blood samples were collected from female patients histologically diagnosed with BC, and 111 female controls were recruited from non-cancer subjects. Genotyping was performed applying the PCR-RFLP method, and all statistical analyzes were conducted using SPSS, version 25.0. Comparison of characteristics and clinicopathological features between ERCC2 rs13181 and ERCC4 rs2276466 carriers and non-carriers showed no significant link with BC. Analysis of ERCC2 rs13181 with the risk of BC showed that the GG genotype and G allele carriers showed a fourfold and 1.78-fold higher risk (OR 4.00, P = 0.001 and OR 1.78, P = 0.002) that are statistically significant. In addition, the patients with combined TG+GG genotype revealed a 2.09-fold increased chance (OR 2.09, P = 0.020) BC development. Analysis of recessive model (GG vs. TT+TG) also depicted 2.74-times significantly higher risk (OR 2.74, P = 0.002). On the other hand, ERCC4 rs2276466 polymorphism did not show any significant association with BC (P > 0.05).
CONCLUSIONS: Our findings show that ERCC2 rs13181 is linked to an elevated risk of BC. Our study also shows that ERCC4 rs2276466 polymorphism has no substantial risk of BC in the Bangladeshi population.

Genetic variants in genes involved in the distribution, metabolism, accumulation or repair of lesions are likely to influence the response of drugs used in the treatment of Head and Neck Cancer (HNC). We examine the effect of 36 SNPs on clinical outcomes in patients with locally advanced HNC who were receiving platinum-based chemoradiotherapy (CRT).
These SNPs were genotyped in 110 patients using the iPLEX Gold assay on the MassARRAY method in blood DNA samples and used Kaplan-Meier and Cox regression analyses to compare genotype groups with the survival.
Two SNPs, rs717620 (ABCC2) and rs12934241 (MMP2) were strongly associated with overall survival (OS) and disease-free survival (DFS). At a median follow-up of 64.4 months, the allele A of rs717620 (ABCC2) had an increased risk of disease progression {hazard ratio [HR] = 1.79, p = 0.0018} and death (HR = 2.0, p = 0.00027). ABCC2 was associated with OS after a Bonferroni adjustment for multiple testing. The MMP2 rs12934241-T allele was associated with an increased risk of worse OS and DFS (p = 0.0098 and p = 0.0015, respectively). One SNP of ABCB1 and three SNPs located in the ERCC2 gene showed an association with response in the subgroup of HNC patients treated with definitive CRT.
Our findings highlight the potential usefulness of SNPs in different genes involved in drug metabolism and repair DNA to predict the response and survival to CRT. ABCC2 is a potential predictor of OS in patients with HNC.

BACKGROUND: Patients with lung cancer (LC) have a poor quality of life (QoL) and easily suffer from psychological diseases. Previous studies focused less on the relationship between genetic factors and QoL, depression, and anxiety status in LC patients. The current study is intended to explore the relationship between SNPs and haplotypes of ERCC1 and ERCC2 and the QoL, depression and anxiety status of patients with LC.
METHODS: QoL, depression and anxiety status were assessed in 291 LC patients using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), SDS and SAS. Nine tag SNPs of ERCC1 and ERCC2 were detected using an improved multiplex ligation detection reaction (iMLDR) technique. Haplotype analysis was conducted using the software Haploview 4.2. The association between SNPs or haplotypes and QoL or depression or anxiety in LC patients was analyzed by regression analysis.
RESULTS: ERCC1 rs11615 was associated with emotional functioning (P = 0.027), and ERCC1 rs3212986 was associated with anxiety scores (P = 0.018). ERCC1 rs762562-rs3212986 haplotype was associated with cognitive function (P = 0.029), somatic function (P = 0.014) and dysphagia (OR = 3.32, P = 0.044). Patients with ERCC1 rs3212986-rs11615 AG haplotype had worse cognitive function (adjusted Beta = - 5.42) and somatic function (adjusted Beta = - 6.55) and had severer symptoms of loss of appetite (adjusted OR = 1.67) and dysphagia (adjusted OR = 4.43) (All adjusted P < 0.05). ERCC2 rs13181-rs3916874-rs238416 haplotype was associated with emotional functioning (P = 0.035), pain at other sites (OR 1.88, P = 0.014), chest pain (OR 0.42, P = 0.02), dysphagia (OR 2.82, P = 0.048), and anxiety status (OR 0.23, P = 0.009).
CONCLUSIONS: After adjustment for environmental factors, SNPs and haplotypes of ERCC1 and ERCC2 were associated with different domains of QoL, depression and anxiety in LC patients.

Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used to assess for presence of XPC PAT +/-, XRCC3 Thr241Met, and ERCC2 Lys751Gln DNA repair gene SNPs in peripheral blood from patients with UCB and healthy individuals. One hundred patients and equal number of healthy subjects were enrolled. The XPC PAT +/+ genotype was associated with a 2-fold increased risk of UCB (OR = 2.16; 95%CI: 1.14-4; p = 0.01). The -/+ and +/+ XPC PAT genotypes were more frequently present in patients with multiple versus single tumors (p = 0.01). No association was detected between ERCC2 Lys751Gln genotypes/alleles, and risk for developing UCB. Presence of the XRCC3 TT genotype (OR = 0.14; 95%CI:0.07-0.25; p < 0.01) and of the T allele overall (OR = 0.26; 95%CI:0.16-0.41; p < 0.01) conferred a protective effect against developing UCB. The XPC PAT -/+ and XRCC3 Thr241Met SNPs are associated with predisposition to UCB. The XPC PAT -/+ SNP is also an indicator of bladder tumor multiplicity, which might require a more individualized surveillance and treatment.