BACKGROUND: In Bangladesh, only a fraction of prostate cancer patients are diagnosed annually due to lack of symptom awareness and screening challenges, resulting in high mortality. Aiming to improve screening methods, we evaluated X-ray cross-complementing gene 1 (XRCC1) Arg194Gln and Xeroderma pigmentosum group D (XPD) Lys751Gln polymorphisms to determine their relevance as potential markers for predicting prostate cancer risk, severity and clinical parameters in Bangladeshi population.
RESULTS: This study included 132 prostate cancer patients and 135 healthy controls. Genotype analysis was done from blood samples by the PCR-RFLP method. The XRCC1 Trp/Trp genotype was associated with prostate cancer (ORadj = 5.51; 95% CI = 1.13-26.78; p-value = 0.03) compared to Arg/Arg genotype. No significant association was found between the XPD variants and prostate cancer risk. The XRCC1 Trp/Trp genotype increased prostate cancer risk in smokers and non-smokers but was statistically non-significant. In individuals without a family history of cancer, the XRCC1 Trp/Trp genotype had a non-significant 4.64-fold higher risk (ORadj=4.64; 95% CI = 0.88-24.36; p-value = 0.07), while the XPD Gln/Gln had a 2.66-fold non-significant higher risk (ORadj=2.66; 95% CI = 0.88-8.10; p-value = 0.09). The XRCC1 Trp/Trp variant was associated with hematuria risk, higher mean serum creatinine, and mean prostate-specific antigen (PSA) levels in prostate cancer patients. The XPD Gln/Gln variant was only associated with higher mean serum creatinine levels.
CONCLUSIONS: Our findings suggest that XRCC1 screening may be used as a biomarker for prostate cancer to improve early diagnosis in Bangladesh.

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.

Breast cancer is one of the leading causes of mortality among women. The most frequently encountered tumors are luminal tumors. Associations of polymorphisms in the hOGG1 (rs1052133), APEX1 (rs1130409), XPD (rs13181), SOD2 (rs4880), and CAT (rs1001179) genes were studied in 313 nonsmoking postmenopausal patients with luminal B subtype breast cancer. The control group consisted of 233 healthy nonsmoking postmenopausal women. Statistically significant associations of the XPD and APEX1 gene polymorphisms with the risk of developing luminal B Her2-negative subtype of breast cancer were observed in a log-additive inheritance model, while the CAT gene polymorphism showed an association in a dominant inheritance model (OR = 1.41; CI 95 %: 1.08-1.85; Padj.= 0.011; OR = 1.39; CI 95 %: 1.07-1.81; Padj = 0.013 и OR = 1.70; CI 95 %: 1.19-2.43; Padj = 0.004, respectively). In the group of elderly women (aged 60-74 years), an association of the CAT gene polymorphism with the risk of developing luminal B subtype of breast cancer was found in a log-additive inheritance model (OR = 1.87; 95 % CI: 1.22-2.85; Padj = 0.0024). Using MDR analysis, the most optimal statistically significant 3-locus model of gene-gene interactions in the development of luminal B Her2-negative subtype breast cancer was found. MDR analysis also showed a close interaction and mutual enhancement of effects between the APEX1 and SOD2 loci and the independence of the effects of these loci from the CAT locus in the formation of luminal B subtype breast cancer.
Онкологические заболевания молочной железы – одна из ведущих причин смертности у женщин. Рак молочной железы относится к числу распространенных мультифакториальных полигенных заболеваний, реализующихся в результате сочетанного взаимодействия генетических и средовых факторов. Наиболее часто встречаются люминальные опухоли. Люминальный подтип В рака молочной железы характеризуется худшим прогнозом и ранними рецидивами. Для изучения генетических факторов риска развития злокачественных новообразований молочной железы необходимо определить полиморфные варианты генов, играющих важную роль в канцерогенезе, к числу которых относятся гены репарации ДНК и системы антиоксидантной защиты. Изучены ассоциации полиморфизмов генов hOGG1 (rs1052133), APEX1 (rs1130409), XPD (rs13181), SOD2 (rs4880) и CAT (rs1001179) у 313 некурящих пациенток в постменопаузе с диагнозом люминального подтипа В Her2-негативного рака молочной железы. В контрольную группу вошли 233 здоровые некурящие женщины в постменопаузе. Зарегистрированы с поправкой на возраст статистически значимые ассоциации полиморфных вариантов генов XPD (rs13181) и APEX1 (rs1130409) с риском развития люминального подтипа В Her2-негативного рака молочной железы в лог-аддитивной модели наследования, гена CAT (rs1001179) – в доминантной модели OR = 1.41; CI 95 %: 1.08–1.85; Padj = 0.011; OR = 1.39; CI 95 %: 1.07–1.81; Padj = 0.013 и OR = 1.70; CI 95 %: 1.19–2.43; Padj = 0.004 соответственно). В группе женщин пожилого возраста (60–74 года) выявлена ассоциация вариантов гена CAT (rs1001179) с риском развития рака молочной железы в лог-аддитивной модели наследования (OR = 1.87; CI 95 %: 1.22–2.85; Padj = 0.0024). С помощью MDR-анализа найдена наиболее оптимальная статистически значимая 3-локусная модель межгенных взаимодействий при развитии онкозаболеваний молочной железы люминального подтипа В. MDR-анализ показал также тесное взаимодействие и взаимное усиление эффектов между локусами APEX1 и SOD2 и независимость эффектов данных локусов от эффекта локуса САТ при формировании люминального подтипа В рака молочной железы.

OBJECTIVE: Single nucleotide polymorphisms (SNPs) are common in genes and can lead to dysregulation of gene expression in tissues, which can affect carcinogenesis. Many studies reporting the association between xeroderma pigmentosum group D (XPD) polymorphisms of rs13181 and rs1799793 with oral cancer risk, but with conflicting and inconclusive results.
METHODS: We performed a comprehensive and systematic search through the PubMed, Elsevier, Web of science, and Embase databases, twelve studies were included in the meta-analysis to determine whether XPD rs13181 and rs1799793 polymorphism contributed to the risk of oral cancer.
RESULTS: The pooled date indicated a significant association between the rs13181 polymorphism and oral cancer risk for the allele comparison model (odds ratio, OR = 1.60, 95% confidence intervals, CI = 1.09-2.35, P = 0.02), the dominant model (OR = 1.74, 95% CI = 1.08-2.82, P = 0.02), and the heterozygote model (OR = 1.59, 95% CI = 1.02-2.49, P = 0.04). For the XPD rs1799793 polymorphism, it is not associated with the incidence of oral cancer under any model. Subgroup analyses based on ethnicity indicated that the rs13181 polymorphism increased the risk of oral cancer among Asians according to the allele comparison model (OR = 1.97, 95% CI = 1.10-3.51, P = 0.02), the dominant model (OR = 2.35, 95% CI = 1.25-4.44, P = 0.008), the heterozygote model (OR = 2.05, 95% CI = 1.15-3.66, P = 0.01), and the homozygous model (OR = 2.47, 95% CI = 1.06-5.76, P = 0.04).
CONCLUSIONS: Our meta-analysis suggests a positive correlation between XPD rs13181polymorphism and the development of oral cancer among Asians, but a negative correlation among Caucasians populations.

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15-2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42-0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19-0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development.

BACKGROUND: The present study was planned to investigate possible association of single nucleotide polymorphisms (SNPs) of nucleotide excision repair (NER) genes such as XPC, XPD, XPG with acute radiation induced toxicities such as skin reactions and oral mucositis in normal tissue from head and neck cancer (HNC) patients receiving radiotherapy.  Methods: Two hundred and fifty HNC patients receiving radiotherapy were enrolled in this study and the acute toxicity reactions and radiation response were recorded. Association of SNPs rs2228001 of XPC, rs238406, rs13181 of XPD and rs17655 of XPG gene with normal tissue reactions in the form of dermatitis and mucositis were studied by PCR-RFLP and direct DNA sequencing.
RESULTS: The results of univariate analysis of SNPs of XPC, XPD and XPG showed that XPC polymorphism at codon 939 of exon 15 (A>C) was not associated with dermatitis (OR=0.30, 95% CI: 0.06-1.39; p=0.125), or oral mucositis (OR=1.14, 95% CI: 0.41-3.20; p=0.793). The XPD codon 156 of exon 6 (C>A) and codon 751 of exon-23 A>C) polymorphism showed no association with radiosensitivity in HNC patients (OR=1.50, 95% CI: 0.60-3.71; p=0.080) for dermatitis, (OR=1.54, 95% CI: 0.66-3.61; p=0.312) for oral mucositis. The 1104 Asp variant genotype or allele of XPG (OR=1.35 95% CI: 0.50-3.64; p=0.541) showed no association with degree of radiotherapy associated dermatitis or mucositis (OR=0.80, 95% CI: 0.32-2.03; p=0.648) in HNC patients. The variant C allele of 2920 A/C genotype of XPC gene at codon 939 of exon 15, found protective with developing skin reactions with grade >1 (OR=0.60, 95% CI: 0.36-0.97; p=0.039) in HNC patients treated with radiotherapy.
CONCLUSIONS: The results obtained in this study concluded that the SNPs rs2228001of XPC, rs238406, rs13181 SNPs of XPD and rs17655 SNP of XPG are not associated with normal tissue toxicity in HNC patients treated with radiotherapy. Radiotherapy with high radiation dose was significantly associated with oral mucositis in response to radiotherapy.

UNASSIGNED: Glioma is one of the central nervous system (CNS) tumors in children, accounting for 80% of malignant brain tumors. Nucleotide excision repair (NER) is a vital pathway during DNA damage repair progression. Xeroderma pigmentosum group D (XPD) or excision repair cross-complementing group 2 (ERCC2) is a critical factor in the NER pathway, playing an indispensable role in the DNA repair process. Therefore, the genetic variants in XPD may be associated with carcinogenesis induced by defects in DNA repair.
UNASSIGNED: We are the first to conduct a multi-center case-control study to investigate the correlation between XPD gene polymorphisms and pediatric glioma risk. We chose three single nucleotide polymorphisms and genotyped them using the TaqMan assay.
UNASSIGNED: Although there is no significant association of these genetic variations with glioma susceptibility, the stratified analysis revealed that in the subtype of astrocytic tumors, the rs13181 TG/GG genotype enhanced glioma risk than the TT genotype, and carriers with two to three genotypes also elevated the tumor risk than 0-1 genotypes.
UNASSIGNED: In conclusion, our findings provided an insight into the impact of XPD genetic variants on glioma risk.

Nucleotide excision repair (NER) is a major DNA repair pathway conserved from bacteria to humans. Various DNA helicases, a group of enzymes capable of separating DNA duplex into two strands through ATP binding and hydrolysis, are required by NER to unwind the DNA duplex around the lesion to create a repair bubble and for damage verification and removal. In prokaryotes, UvrB helicase is required for repair bubble formation and damage verification, while UvrD helicase is responsible for the removal of the excised damage containing single-strand (ss) DNA fragment. In addition, UvrD facilitates transcription-coupled repair (TCR) by backtracking RNA polymerase stalled at the lesion. In eukaryotes, two helicases XPB and XPD from the transcription factor TFIIH complex fulfill the helicase requirements of NER. Interestingly, homologs of all these four helicases UvrB, UvrD, XPB, and XPD have been identified in archaea. This review summarizes our current understanding about the structure, function, and mechanism of these four helicases.

BACKGROUND: The effective maintenance of genome integrity and fidelity is vital for the normal function of our tissues and organs, and the prevention of diseases. DNA repair pathways maintain genome stability, and the adequacy of genes acting in these pathways is essential for disease suppression and direct treatment responses. Chronic kidney disease is characterized by high levels of genomic damage. In this study, we examined the expression levels of the xeroderma pigmentosum group D (XPD) gene, which plays a role in the nucleotide excision repair (NER) repair mechanism, and the expression levels of miR-145 and miR-770 genes, which play a role in the regulation of the expression of the XPD gene, in hemodialysis patients with (n = 42) and without malignancy (n = 9) in pre- and post-dialysis conditions. We also evaluated these values with the clinical findings of the patients.
RESULTS: Gene expression analysis was performed by real-time polymerase chain reaction (qRT-PCR). Compared to the individuals with normal kidney function (2.06 ± 0.32), the XPD gene expression was lower in the pre-dialysis condition both in hemodialysis patients without cancer (1.24 ± 0.18; p = 0.02) and in hemodialysis patients with cancer (0.82 ± 0.114; p = 0.001). On the other hand, we found that miR-145 and miR-770 expression levels were high in both groups. We also found that expression levels were affected by dialysis processes. A statistically significant positive correlation was found between miR-145 and mir770 expression levels in the pre-dialysis group of patients with (r=-0.988. p = 0.0001) and without (r=-0.934. p = 0.0001) malignancy.
CONCLUSIONS: Studies on DNA damage repair in the kidney will help develop strategies to protect kidney function against kidney diseases.