Oroxylin A (OA), a natural compound extracted from Scutellaria baicalensis, demonstrates preventive potential against ultraviolet B (UVB)-induced non-melanoma skin cancer (NMSC), the most prevalent cancer worldwide with increasing incidence. Utilizing SKH-1 hairless mice exposed to UVB, this study showed that OA delayed NMSC onset and alleviated acute skin damage. Mechanistic investigations revealed its dual action: inhibiting inflammation and enhancing nucleotide excision repair (NER) by stabilizing XPA, a crucial deoxyribonucleic acid (DNA) repair protein. This stabilization occurred through OA's interaction with glucose-regulated protein 94 (GRP94), which disrupted murine double minute 2 (MDM2)-mediated XPA ubiquitination and proteasomal degradation. By maintaining XPA levels, OA expedited photoproduct clearance and diminished genomic instability, ultimately impeding NMSC development. These findings suggest OA as a promising chemopreventive agent targeting the GRP94/MDM2-XPA axis to counteract UVB-induced carcinogenesis.
Animals ; Ultraviolet Rays/adverse effects* ; Skin Neoplasms/prevention & control* ; Flavonoids/pharmacology* ; Mice ; Xeroderma Pigmentosum Group A Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-mdm2/genetics* ; DNA Repair/drug effects* ; Scutellaria baicalensis/chemistry* ; Mice, Hairless ; Skin/radiation effects*

OBJECTIVE: To explore the clinical presentation and genetic etiology of a case with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma. METHODS: A male patient with Xeroderma pigmentosum treated at Xinxiang Central Hospital in October 2022 was selected as study subject. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of his family members. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2021-167). RESULTS: Magnetic resonance imaging showed that the patient has a solid soft tissue mass in the anterior and lower part of his right eyeball and a small nodule on the left nasal wing. Histopathological biopsy showed that the periocular tumor was basal cell carcinoma in conjunct with malignant melanoma, and the nasal wing tumor was basal cell carcinoma. WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XPC gene, namely c.2391delT (p.F797Lfs*11) and IVS1+1G>A, which were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were rated as likely pathogenic (PVS1+PM2_Supporting+PM3) and pathogenic (PVS1+PM2_Supporting+PM3+PP5), respectively. The c.2391delT variant was unreported previously. Bioinformatic analysis suggests that it could significantly affect the tertiary structure of XPC protein. CONCLUSION The c.2391delT(p.F797Lfs*11) and IVS1+1G>A compound heterozygous variants probably underlay the pathogenesis in this patient. The detection of the novel variant has enriched the mutational spectrum of the XPC gene.
Humans ; Male ; Xeroderma Pigmentosum/genetics* ; Basal Cell Carcinoma/genetics* ; DNA-Binding Proteins/genetics* ; Melanoma/genetics* ; Mutation ; Skin Neoplasms/genetics* ; Middle Aged ; Exome Sequencing ; Pedigree

Ultraviolet light(UV)-sensitive disorders refer to a group of diseases due to damages to the nucleotide excision repair mechanism which cannot effectively repair DNA damage caused by ultraviolet radiation. The inheritance pattern of such diseases, mainly including xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, is autosomal recessive and known to involve 13 genes. As proteins encoded by such genes are involved in DNA repair and transcription pathways. There is overlap between the symptoms of such diseases, and their genotype - phenotype correlations are quite complex. To facilitate genetic and prenatal diagnosis for such diseases, a summary of the research progress is provided, which mainly focused on mutation research and genotype - phenotype correlation studies. We also propose a strategy for their genetic diagnosis based on recent findings of our group.
Biomedical Research ; methods ; trends ; Cockayne Syndrome ; genetics ; DNA Damage ; DNA Repair ; genetics ; Genetic Predisposition to Disease ; genetics ; Humans ; Skin ; metabolism ; pathology ; radiation effects ; Trichothiodystrophy Syndromes ; genetics ; Ultraviolet Rays ; Xeroderma Pigmentosum ; genetics

Xeroderma pigmentosum (XP) is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patient-specific induced pluripotent stem cells (iPSCs) harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells (NSCs) or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clarify the molecular mechanisms of neurological abnormalities in the XP patients.
DNA Damage ; DNA Repair ; DNA-Binding Proteins ; genetics ; metabolism ; Female ; Humans ; Induced Pluripotent Stem Cells ; metabolism ; pathology ; Male ; Models, Biological ; Mutation ; Neural Stem Cells ; metabolism ; pathology ; Xeroderma Pigmentosum ; genetics ; metabolism ; pathology

OBJECTIVETo explore the relationship of polymorphisms in the xeroderma pigmentosum group D (XPD) gene and the glutathione-S transferees M1 (GSTM1) gene with susceptibility to primary hepatic carcinoma (PHC) in Tibetans from the Qinghai region.

METHODSThis case-control study compared equal groups (n=102 each) of patients with PHC and healthy individuals recruited from Qinghai, Tibet.PCR and denaturing high-performance liquid chromatography (DHPLC) was used to detect each participant's genotypes for the XPD and GSTM1 genes.Non-conditional logistic regression modeling was used in multivariate analysis to evaluate the predictive value for PHC, to compare the risk of different genotypes for PHC, and to assess the risk of gene polymorphisms and environmental factors for PHC.

RESULTSSix factors, including smoking, carnivorous diet, alcohol consumption, hepatitis B virus (HBV) infection, immediate family members with HBV infection and immediate family members with history of PHC, were included in the logistic regression model (alpha =0.05).The XPD751C mutation genotype distribution frequencies were significantly higher in the cases than in the controls (21.6% vs. 10.8%, P=0.036). The risk of PHC increased 2.275 times (95% CI, 1.04-4.98). The frequencies of the GSTM1 genotype were remarkably higher in the cases than in the controls (60.4% vs. 39.6%, P=0.017), suggesting this as an exposure factor. Individuals with the GSTM1 genotype had 1.963 times higher risk of PHC than individuals without the GSTM1 genotype (95% CI, 1.124-3.428). With both the XPD751C mutation and the GSTM1 genotype as exposure factors, the risk incidence increased to 3.030 times (95% CI, 1.165-7.881), indicating that the combined genotypes have a synergistic effect.Application of unconditioned logistic stepwise regression analysis of the genotypes and environmental risk factors showed an interaction between the XPD751C mutation and HBV infection, alcohol consumption and immediate family members with history of PHC. In addition, an interaction between the GSTM1 genotype and HBV infection was found.

CONCLUSIONAlcohol consumption, HBV infection and the presence of immediate family members with HBV infection are the main environmental risk factors of PHC in Qinghai Tibetans.Qinghai Tibetans who carry the XPD751C gene mutation and the GSTM 1 genotype are at increased risk of PHC, compared to individuals carrying only one or the other.The XPD751C mutation may increase risk of PHC when combined with the environmental factors.

Alcohol Drinking ; Carcinoma, Hepatocellular ; genetics ; Case-Control Studies ; Genetic Predisposition to Disease ; Genotype ; Glutathione ; Glutathione Transferase ; genetics ; Humans ; Incidence ; Liver Neoplasms ; genetics ; Logistic Models ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Risk Factors ; Smoking ; Tibet ; Xeroderma Pigmentosum Group D Protein ; genetics

OBJECTIVETo explore the influence of the DNA repair gene ERCC2 single nucleotide polymorphisms (SNPs) rs13181, rs1618536, and rs1799793 on male idiopathic infertility in Ningxia, China.

METHODSUsing MassArray, we conducted a case-control study and genotyped three ERCC2 SNPs rs13181, rs1618536, and rs1799793 for 351 males (aged 31.0 +/- 4.2 years) with idiopathic infertility and another 327 normal fertile men (aged 33.0 +/- 5.9 years) as controls.

RESULTSThe ERCC2 AnyG-anyA-anyA genotypes were significantly associated with an increased risk of idiopathic infertility (OR 0.414, 95% CI 0.176 - 0.970), while the three single ERCC2 SNPs rs13181, rs1618536, and rs1799793 showed no significant differences between the cases and controls (P > 0.05).

CONCLUSIONThe ERCC2 SNPs rs13181, rs1618536, and rs1799793 play a role of interaction in male idiopathic infertility in Ningxia, contributing to the risk of the disease.

Adult ; Case-Control Studies ; China ; DNA Repair ; Genotype ; Humans ; Infertility, Male ; genetics ; Male ; Polymorphism, Single Nucleotide ; Xeroderma Pigmentosum Group D Protein ; genetics

OBJECTIVE: To analyze the association between genetic polymorphisms of DNA repair genes of XPD (751 Lys/Gln), XPC (PAT)and susceptibility to laryngeal carcinoma. To explore the effect between DNA repair genes of XPD (751 Lys/Gln), XPC (PAT) and carcinogenesis of LSCC(laryngeal squamous cell carcinoma). METHOD: A case-control study was conducted involving 233 LSCC patients and 102 healthy controls to investigate the association between polymorphisms of XPD(751 Lys/Gln), XPC (PAT) and LSCC. All blood samples of the Han people from the Guang Dong Zone was analysze with methods of PCR, PCR-RFLP, ASA and the technique of checking DNA sequencing with sequenator. We explored the association between polymorphisms and the clinical pathologic characteristic of LSCC. The data was compute with SPSS13.0. Odds Ratios (ORs) with 95% CI for relevancy intensity were calculated using binary logistic regression analysis. REULT: There is no difference of the frequency of XPC-PAT and XPD (751 Lys/Gln) genotype between in LSCC and in healthy contradistinguish (P > 0.05). CONCLUSION There may be no association between the susceptibility to laryngeal carcinoma and the genotype of XPC-PAT and XPD (751 Lys/Gln).
Carcinoma, Squamous Cell ; genetics ; Case-Control Studies ; DNA Repair ; genetics ; DNA-Binding Proteins ; genetics ; Female ; Genotype ; Humans ; Laryngeal Neoplasms ; genetics ; Male ; Polymorphism, Genetic ; Sequence Analysis, DNA ; Xeroderma Pigmentosum Group D Protein ; genetics

OBJECTIVETo explore the association between polymorphisms in the DNA repair gene, xeroderma pigmentosum group D (XPD), and development of hepatocellular carcinoma (HCC) in the Chinese population by performing a systematic review of the previously published clinical data.

METHODA comprehensive literature search of the BIOSIS Previews and PubMed databases was carried out to identify all case-control studies of XPD polymorphisms and HCC risk. Meta-analysis was conducted to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs) of developing HCC for carriers of the various XPD polymorphisms.

RESULTSSix case-control studies were selected for this meta-analysis, and comprised a total of 3424 HCC cases and 3636 controls. The pooled ORs (95% CIs) of XPD codon 751 and 312 allelomorphs were 1.25 (0.70 to 2.24) and 0.85 (0.58 to 1.25), respectively. Compared with the XPD wild-type homozygote Lys/Lys genotype of codon 751, the pooled OR (95% CI) of Lys/G1n + Gln/Gln genotypes for HCC risk was 1.31 (0.71 to 2.42). Compared with the XPD wild-type homozygote Asp/Asp genotype of codon 312, the pooled OR (95% CI) of Asp/Asn + Asn/Asn genotypes for HCC risk was 1.19 (0.73 to 1.95).

CONCLUSIONPolymorphisms in the XPD codons 751 and 312 are not associated with HCC risk in the Chinese population.

Carcinoma, Hepatocellular ; genetics ; Codon ; genetics ; DNA Repair ; Genetic Predisposition to Disease ; Humans ; Liver Neoplasms ; genetics ; Polymorphism, Genetic ; Xeroderma Pigmentosum Group D Protein ; genetics

OBJECTIVETo investigate whether single nucleotide polymorphism (SNP) in DNA repair gene XPD751 is associated with sensitivity and time to progression (TTP) for platinum-containing combination chemotherapy in advanced colorectal carcinoma.

METHODSA total of 98 patients pathologically diagnosed as advanced colorectal cancer were treated with FOLFOX chemotherapy. TheDNA of peripheral blood-leukocytes was obtained before treatment, and XPD genetype was detected by PCR-RFLP analysis.

RESULTSThe frequency of XPD751 Lys/lys was 76 cases (77.6%), lys/Gln 17 cases (17.4%), and Gln/Gln genetype 5 cases (5.1%). The effective rate of FOLFOX chemotherapy among patients with XPD751 Lys/lys was 50.0%, lys/Gln 29.4%, and Gln/Gln genetypes 20.0%. The difference between Lys/lys and lys/Gln was statistically significant, χ(2) = 4.04, P < 0.05. The results indicated that the failure of chemotherapy in patients with Lys/Lys genetype was 3.8-fold to those with Lys/Gln, by adjusting of gender, age, and tumor metastasis (OR = 3.800). The MTTP of the 98 patients was 10.1 months. The MTTP was 11.3 months for patients with Lys/Lys genotypes of XPD751 gene and 2.9 months for patients with Lys/Gln and Gln/Gln genotypes of XPD751 gene, the difference between Lys/Lys and at least one Gln was significant (P < 0.05).

CONCLUSIONSSingle nucleotide polymorphism of XPD751 correlates with the clinical response to FOLFOX chemotherapy. XPD751 genetic polymorphisms may be associated with TTP of advanced colorectal carcinoma patients treated with oxaliplatin as the first line chemotherapy. XPD751 genotype detected by the PCR-RFLP method may be a predictor of prognosis for FOLFOX chemotherapy.

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; DNA Repair ; Disease Progression ; Female ; Fluorouracil ; therapeutic use ; Follow-Up Studies ; Genotype ; Humans ; Leucovorin ; therapeutic use ; Male ; Middle Aged ; Neoplasm Staging ; Organoplatinum Compounds ; therapeutic use ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Xeroderma Pigmentosum Group D Protein ; genetics

BACKGROUND AND OBJECTIVEIt has been proven that close relation was existed between XPD polymorphism G312A and lung cancer risk. However, some of the results are not consistent. The aim of this study is to explore the impact of DNA repair gene XPD polymorphism G312A on lung cancer risk.

METHODSThe literatures eligible from PUBMED, EMBASE, CNKI and WANGFANG database were enrolled in the meta-analysis. Heterogeneity among combined studies was assessed. The pooled OR and 95%CI were calculated. The sensitivity analysis and the publication bias were evaluated by RevMan 5.0 and STATA 11.0.

RESULTSThere were 6554 cases and 8322 controls from 18 studies included in the meta-analysis. In total, individuals with 312A allele and 312AA genotype showed increased lung cancer risk (A vs. G: OR = 1.06, 95% CI: 1.00-1.12; AA vs. AG+GG: OR = 1.20, 95% CI: 1.06-1.36; AA vs. GG: OR = 1.19, 95% CI: 1.04-1.36). In Asians, individuals with 312AA genotype showed 6.15 fold and 6.20 fold increased lung cancer risk in recessive genetic model and homogenous contrast respectively (AA vs. AG+GG: OR = 7.15, 95% CI: 1.90-26.94; AA vs. GG: OR = 7.20, 95% CI: 1.91-27.15). In Caucasians, individuals with 312AA genotype showed a 15% increased lung cancer risk (OR = 1.15, 95% CI: 1.01-1.31).

CONCLUSIONXPD 312A allele is risk allele for lung cancer. Individuals with AA genotype have higher risk of lung cancer, especially in Asians.

Genotype ; Humans ; Lung Neoplasms ; etiology ; genetics ; Odds Ratio ; Polymorphism, Genetic ; Xeroderma Pigmentosum Group D Protein ; genetics