Xeroderma Pigmentosum Group G Gene Research Articles

Comparative evaluation of XPD and XPG gene polymorphism in oral squamous cell carcinoma and tobacco chewers: An observational study.

The study indicated that XPD and XPG gene polymorphism is associated with the development of oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma. Xeroderma pigmentosa (XP) is a part of the complex DNA repair system. Xeroderma pigmentosum group G (XPG) and xeroderma pigmentosum group D (XPD) gene function in the nucleotide excision repair (NER) pathway. XPG and/or XPD gene alterations can cause defective DNA repair efficiency which ultimately leads to genomic instability and carcinogenesis. Thus, this study helps in early detection of OPMDs among individuals who have not yet developed any oral lesions and also helps in the management of oral squamous cell carcinoma as if XP gene polymorphism is known. The aim of the study was to evaluate the expression of XPD and XPG gene polymorphism in oral squamous cell carcinoma cases. The study also had the objective to evaluate and compare the expression of XPG and XPD gene polymorphism in oral squamous cell carcinoma (OSCC) cases, tobacco chewers without any oral lesions, and normal healthy individuals without any habit. A total of 150 subjects were included in the study and genotyped for the expression of XPD (AC) and XPG (GC) gene polymorphism using polymerase chain reaction (PCR) and agarose gel electrophoresis method. XPD genotype for the study shows that most of the cases of OSCC show heterozygous (AC) genotype (64%), whereas in tobacco chewers without any oral lesions wild (AA) genotype (54%) is more common than other types. XPG genotype for the study shows that wild (GG) type is the most dominant genotype both in OSCC cases (78%) and tobacco chewers without any oral lesion (56%). The study shows the association of XPD and XPG gene polymorphism with the risk of developing OPMDs and oral cancer.

XPG gene polymorphisms and glioma susceptibility: a two-centre case–control study

ABSTRACT Background: Glioma, the most common tumour in children next to leukaemia, is difficult to treat, with a poor prognosis and high recurrence rate. Xeroderma pigmentosum group G (XPG) plays a key role in the nucleotide excision repair pathway, which may modulate individual susceptibility to developing cancer. We hypothesized links between XPG variants and glioma in children. Methods: We tested our hypothesis in a study comparing 171 glioma cases with 228 age and sex matched controls, determining XPG polymorphisms rs2094258 C > T, rs751402 C > T, rs2296147 T > C, rs1047768 T > C, rs873601 G > A by standard molecular genetic methods. Results: rs2094258 C > T was associated with a decreased glioma risk, but carrying the rs1047768 C or rs873601 A allele brought an increased risk. Subjects carrying 5 risk genotypes had a significantly increased glioma risk at an adjusted odds ratio of 1.97 (95% confidence Interval 1.26–3.08)(p = 0.003) when compared with those carrying 0–4 risk genotypes. Furthermore, children with 5 risk genotypes had a higher glioma risk when aged >60 months, were more likely to be male, and with subtypes of astrocytic tumours, and low-grade clinical stage, when compared to those with 0–4 risk genotypes. Preliminary functional exploration suggested that rs2094258 is linked with the expression of its surrounding genes in the expression quantitative trait locus analysis. Conclusion: Certain variants of XPG are risk factors for paediatric glioma, and so may be useful in early diagnosis.

Modulation of DNA damage by XPF, XPG and ERCC1 gene polymorphisms in pesticide-exposed agricultural workers of Punjab, North-West India

Inter-individual variations in DNA repair capacity (DRC) for repairing pesticide-induced DNA oxidation damage may influence adverse health outcomes. We aimed to evaluate whether polymorphisms in genes involved in nucleotide excision repair (NER) pathway could modulate DNA damage in pesticide-exposed agricultural workers. Xeroderma pigmentosum group F (XPF) (Arg415Gln, G1244A, rs1800067), xeroderma pigmentosum group G (XPG) (Asp1104His, G3507C, rs17655), excision repair cross complementation group 1 (ERCC1) (3′UTR, C8092A, rs3212986) and ERCC1 (Asn118Asn, C19007T, rs11615) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique in 225 pesticide-exposed agricultural workers and 225 controls from Punjab, North-West India. The assessment of DNA damage was carried out by alkaline comet assay. Kruskal-Wallis test was used to evaluate the association of gene polymorphisms in NER pathway with DNA damage. Pesticide-exposed agricultural workers carrying variant XPF Gln/Gln (AA) genotype showed higher comet tail length (p < 0.01) than wild type Arg/Arg (GG) genotype. The comet tail length (p < 0.01) was found to be significantly increased in exposed agricultural workers carrying XPG His/His (CC) genotype than wild-type Asp/Asp (GG) genotype. In relation to the individuals carrying wild type ERCC1 3′UTR CC genotype, exposed individuals with variant ERCC1 3′UTR CA genotype showed elevation in the comet tail length (p = 0.029). However, we found no association of ERCC1 Asn118Asn (C19007T) genotype with DNA damage. These results indicate that XPF, XPG and ERCC1 genes of NER pathway may modulate the efficacy of the DNA repair system against pesticide exposure in our population.

Human XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations

Xeroderma pigmentosum group G (XPG) protein is both a functional partner in multiple DNA damage responses (DDR) and a pathway coordinator and structure-specific endonuclease in nucleotide excision repair (NER). Different mutations in the XPG gene ERCC5 lead to either of two distinct human diseases: Cancer-prone xeroderma pigmentosum (XP-G) or the fatal neurodevelopmental disorder Cockayne syndrome (XP-G/CS). To address the enigmatic structural mechanism for these differing disease phenotypes and for XPG's role in multiple DDRs, here we determined the crystal structure of human XPG catalytic domain (XPGcat), revealing XPG-specific features for its activities and regulation. Furthermore, XPG DNA binding elements conserved with FEN1 superfamily members enable insights on DNA interactions. Notably, all but one of the known pathogenic point mutations map to XPGcat, and both XP-G and XP-G/CS mutations destabilize XPG and reduce its cellular protein levels. Mapping the distinct mutation classes provides structure-based predictions for disease phenotypes: Residues mutated in XP-G are positioned to reduce local stability and NER activity, whereas residues mutated in XP-G/CS have implied long-range structural defects that would likely disrupt stability of the whole protein, and thus interfere with its functional interactions. Combined data from crystallography, biochemistry, small angle X-ray scattering, and electron microscopy unveil an XPG homodimer that binds, unstacks, and sculpts duplex DNA at internal unpaired regions (bubbles) into strongly bent structures, and suggest how XPG complexes may bind both NER bubble junctions and replication forks. Collective results support XPG scaffolding and DNA sculpting functions in multiple DDR processes to maintain genome stability.

Association of XPG rs2094258 polymorphism with gastric cancer prognosis.

BACKGROUNDThe xeroderma pigmentosum group G (XPG) gene at chromosome 13q33 consists of 15 exons, which may be related to the occurrence and development of gastric cancer (GC).AIMTo examine the association of several common single nucleotide polymorphisms (SNPs) of the XPG gene with GC risk and survival.METHODSFive SNPs of XPG (rs2094258, rs751402, rs873601, rs2296147, and rs1047768) were genotyped by PCR restriction fragment length polymorphism in 956 histologically confirmed GC cases and 1012 controls in North China. GC patients were followed for survival status and, if deceased, cause of death. Logistic regression and Cox regression were used for analysing associations of XPG SNPs with risk of GC and prognosis, respectively. For rs2094258, heterozygous model (CT vs CC), homozygous model (TT vs CC), recessive model (TT vs CT + CC), and dominant model (TT + CT vs CC) were analyzed.RESULTSNone of the examined loci were statistically associated with GC risk, although rs2296147 was marginally associated with GC risk (P = 0.050). GC patients with the rs2094258 CT + CC genotype showed worse survival than those with the TT genotype (log-rank test, P = 0.028), and patients with the CC genotype had a tendency of unfavourable prognosis compared with those with the TT + CT genotype (log-rank test, P = 0.039). The increase in C alleles of rs2094258 [hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.02-1.45, P = 0.037] were associated with the long-term survival of GC cases. Other risk factors for survival included tumor differentiation (HR = 4.51, 95%CI: 1.99-8.23, P < 0.001), lymphovascular invasion (HR = 1.97, 95%CI: 1.44-3.01, P < 0.001), and use of chemotherapy (HR = 0.81, 95%CI: 0.63-0.98, P = 0.041).CONCLUSIONThe XPG rs2094258 polymorphism may be associated with overall survival in GC patients.

XPG rs17655 G>C polymorphism associated with cancer risk: evidence from 60 studies.

Xeroderma pigmentosum group G (XPG), a key component in nucleotide excision repair pathway, functions to cut DNA lesions during DNA repair. Genetic variations that alter DNA repair gene expression or function may decrease DNA repair ability and impair genome integrity, thereby predisposing to cancer. The association between XPG rs17655 G>C polymorphism and cancer risk has been investigated extensively, but the results remain contradictory. To get a more accurate conclusion, we performed a comprehensive meta-analysis of 60 case-control studies, involving 27,098 cancer cases and 30,535 healthy controls. Crude odds ratios (ORs) and 95% confidence interval (CIs) were calculated to determine the association of interest. Pooled analysis indicated that the XPG rs17655 G>C polymorphism increased the risk of overall cancer (CC vs. GG: OR=1.10, 95% CI=1.00-1.20; CG vs. GG: OR=1.06, 95% CI=1.02-1.11; CG+CC vs. GG: OR=1.07, 95% CI=1.02-1.12; C vs. G: OR=1.05, 95% CI=1.01-1.09). Stratification analysis by cancer type further showed that this polymorphism was associated with increased risk of gastric cancer and colorectal cancer. This meta-analysis indicated that the XPG gene rs17655 G>C polymorphism was associated with increased overall cancer risk, especially the risk of gastric cancer and colorectal cancer. Further validation experiments are needed to strength our conclusion.

Association between the XPG gene rs2094258 polymorphism and risk of gastric cancer.

Xeroderma pigmentosum group G (XPG) plays an important role in maintaining the stability and integrity of genomic DNA. Previous studies demonstrate some XPG gene polymorphisms are associated with susceptibility to gastric cancer (GC). The association between XPG rs2094258 polymorphism and GC risk was investigated first by a hospital-based case-control study involving 386 patients and 439 controls and then by a meta-analysis. The polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLR). Xeroderma pigmentosum group G rs2094258 polymorphism was associated with an increased risk of GC in a Chinese population. The meta-analysis did not reveal any significant difference in the overall population. Subgroup analysis of geographic locations showed a significant association between the XPG gene rs2094258 polymorphism and GC risk in Southern China. Stratification analysis further indicated significant associations in hospital-based studies and studies using PCR-RFLR. Xeroderma pigmentosum group G gene rs2094258 polymorphism may be associated with an increased risk of GC in Southern China. Nevertheless, the findings of this meta-analysis should be validated by well-designed large-scale case-control studies among other ethnicities.

Association between the polymorphisms in XPG gene and gastric cancer susceptibility in Chinese populations: A PRISMA-compliant meta-analysis.

Background:Several previous studies were carried out on the association between xeroderma pigmentosum group G (XPG) gene polymorphisms (including rs873601 G>A, rs2094258 C>T, rs2296147 T>C, and rs751402 C>T) and the risk of gastric cancer in Chinese populations. However, their conclusions were not consistent. Therefore, this meta-analysis was performed by us to investigate the association between the 4 potentially functional single nucleotide polymorphisms (SNPs) of XPG gene and gastric cancer risk.Methods:The eligible literatures were identified through PubMed, Embase, Ovid MEDLINE, Web of Science, CNKI, and Wan fang databases up to July 2017. Finally, 5 studies for rs873601, 7 studies for rs2094258, 4 studies for rs2296147, and 8 studies for rs751402 were used for the current meta-analysis.Results:Of the 4 included SNPs, only rs751402 was showed to be associated with the risk of gastric cancer [C vs T, odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.04–1.29; CC + CT vs TT, OR = 1.23, 95% CI = 1.00–1.52; CC vs CT + TT, OR = 1.15, 95% CI = 1.05–1.27; CC vs TT, OR = 1.35, 95% CI = 1.06–1.72; CC vs CT, OR = 1.13, 95% CI = 1.02–1.25].Conclusion:The current meta-analysis demonstrated that the XPG gene polymorphism rs751402 was associated with increased susceptibility to gastric cancer in Chinese populations. However, studies with a larger number of subjects among different ethnic groups are needed to further validate the results.

Association of XPG gene rs751402 polymorphism with gastric cancer risk: a meta-analysis in the Chinese population.

Previous studies have revealed a conflicting relationship of xeroderma pigmentosum group G (XPG) gene polymorphism with gastric cancer (GC) risk. To our knowledge, this is the first meta-analysis to investigate the association between rs751402 mutation located on the XPG promoter region and GC risk. We undertook a meta-analysis by identifying relevant articles from the PubMed, Web of Science and China National Knowledge Infrastructure (CNKI) databases on February 28, 2017. By pooling 9 eligible studies, 3,539 GC cases and 3,948 controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using the fixed-effects or random-effects model depending on the existence of heterogeneity across studies. The population attributable risk (PAR%) was estimated to better understand the public health risk. All included studies had been conducted in China. Significant associations were found between the XPG rs751402 polymorphism and the risk of GC (TT vs. CC: OR = 1.43, 95% CI, 1.11-1.84; CT vs. CC: OR = 1.15, 95% CI, 1.04-1.26; dominant model: OR = 1.17, 95% CI, 1.07-1.29; recessive model: OR = 1.30, 95% CI, 1.05-1.62; T vs. C: OR = 1.18, 95% CI, 1.06-1.32). The estimated PAR% was about 4.9%-8.8%. Funnel plots did not reveal any potential publication bias. The sensitivity analyses showed that the results were relatively robust. This meta-analysis indicates that the XPG rs751402 polymorphism may be a risk factor for GC in the Chinese population.

The Association Between XPG Gene Polymorphism and Gastric Cancer Risk.

Studies exploring the association between the Xeroderma pigmentosum group G (XPG) gene polymorphisms and gastric cancer (GC) risk provide conflicting findings. Thus, this meta-analysis was performed. The PubMed and EMBASE databases were comprehensively searched to identify studies for the inclusion in the meta-analysis. The strength of the association was evaluated by calculating pooled odds ratios and 95% confidence intervals. Nine case-control studies involving 3540 cases and 3953 controls were included in the meta-analysis, which revealed that the XPG rs751402 polymorphism is positively associated with GC risk and could be viewed as a risk factor of GC in three genetic models. The XPG gene rs751402 polymorphism is associated with an increased risk of GC in Chinese Han populations. This finding should be verified by larger studies that include additional ethnic groups.

XPG gene rs751402 C>T polymorphism and cancer risk: Evidence from 22 publications.

The Xeroderma pigmentosum group G (XPG) gene promotes recognition and excision of damaged DNA during the DNA repair process. We conducted a comprehensive search of the MEDLINE, EMBASE, and Chinese Biomedical databases for publications evaluating the association XPG gene rs751402 C>T polymorphism and overall cancer risk. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were adopted to assess the strength of the association. A total of 22 publications encompassing 10538 cases and 10511 control subjects were included in the final meta-analysis. We found the polymorphism to be associated with increased cancer risk (TT vs. CC: OR = 1.18, 95% CI = 1.01–1.38, P = 0.040; CT vs. CC: OR = 1.12, 95% CI = 1.01–1.24, P = 0.040; and CT/TT vs. CC: OR = 1.12, 95% CI = 1.002–1.26, P = 0.045). Stratification by cancer type indicated that this polymorphism may increase the risk of gastric cancer and hepatocellular carcinoma, which was further confirmed by a false-positive report probability analysis. Genotype-based mRNA expression provides further evidence that this polymorphism is associated with altered XPG mRNA expression. This meta-analysis suggests XPG gene rs751402 C>T polymorphism correlates with overall cancer risk, especially for gastric cancer and hepatocellular carcinoma.

XPG gene polymorphisms and cancer susceptibility: evidence from 47 studies.

Xeroderma pigmentosum group G (XPG) is a single-strand-specific DNA endonuclease that functions in the nucleotide excision repair pathway. Genetic variations in XPG gene can alter the DNA repair capacity of this enzyme. We evaluated the associations between six single nucleotide polymorphisms (SNPs) in XPG (rs1047768 T>C, rs2296147 T>C, rs2227869 G>C, rs2094258 C>T, rs751402 C>T, and rs873601 G>A) and cancer risk. Forty-seven studies were identified in searches of the PubMed, Scopus, Web of Science, China National Knowledge Infrastructure, and WanFang databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed or random effects model. We found that rs873601 G>A was associated with an increased overall cancer risk (AA vs. GG: OR = 1.14, 95% CI = 1.06–1.24; GA/AA vs. GG: OR = 1.08, 95% CI = 1.02–1.15; A vs. G: OR = 1.06, 95% CI = 1.02–1.10). In a stratified analysis, rs1047768 T>C was associated with an increased risk of lung cancer, rs2227869 G>C was associated with a decreased risk of cancer in population-based studies, and rs751402 C>T and rs873601 G>A were associated with the risk of gastric cancer. Our data indicate that rs873601 G>A is associated with cancer susceptibility.

Association between genetic variants in the XPG gene and gastric cancer risk in a Southern Chinese population.

Xeroderma pigmentosum group G (XPG) recognizes and excises DNA damage on the 3′ side during the DNA repair process. Previous studies indicated that XPG gene polymorphisms may associate with gastric cancer susceptibility, but results were inconsistent. We evaluated the association of five potentially functional XPG polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C, and rs873601 G>A) with gastric cancer susceptibility in 1142 gastric cancer cases and 1173 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models. Overall, no significant association was detected between any of selected polymorphism and gastric cancer risk. However, we found that individuals carrying 3-4 risk genotypes were at significantly higher risk of gastric cancer than those with 0-2 risk genotypes (OR=1.32, 95% CI=1.04-1.68, P=0.021). The stratification analysis revealed that the cumulative effect of risk genotypes (3-4 vs. 0-2) on gastric cancer were more prominent among subgroups older than 58 years and men. In conclusion, our results indicated that none of the selected XPG polymorphism could significantly alter gastric cancer susceptibility alone. These polymorphisms might collectively confer increased gastric cancer susceptibility. These findings would be strengthened by larger prospective multicenter studies involving different ethnic populations.

XPG rs2296147 T>C polymorphism predicted clinical outcome in colorectal cancer.

Xeroderma pigmentosum group G (XPG), one of key components of nucleotide excision repair pathway (NER), is involved in excision repair of UV-induced DNA damage. Single nucleotide polymorphisms (SNPs) in the XPG gene have been reported to associate with the clinical outcome of various cancer patients. We aimed to assess the impact of four potentially functional SNPs (rs2094258 C>T, rs2296147 T>C, rs751402 G>A, and rs873601 G>A) in the XPG gene on prognosis in colorectal cancer (CRC) patients. A total of 1901 patients diagnosed with pathologically confirmed CRC were genotyped for four XPG polymorphisms. Cox proportional hazards model analysis controlled for several confounding factors was conducted to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Of the four included SNPs, only rs2296147 was shown to significantly affect progression-free survival (PFS) in CRC. Patients carrying rs2296147 CT/TT genotype had a significantly shorter median 10 years PFS than those carrying CC genotype (88.5 months vs. 118.1 months), and an increased progression risk were observed with rs2296147 (HR = 1.324, 95% CI = 1.046–1.667). Moreover, none of the four SNPs were associated with overall survival. In conclusion, our study showed that XPG rs2296147 CT/TT variants conferred significant survival disadvantage in CRC patients in term of PFS. XPG rs2296147 polymorphism could be predictive of unfavorable prognosis of CRC patients.

Association between XPG polymorphisms and stomach cancer susceptibility in a Chinese population.

Xeroderma pigmentosum group G (XPG) protein plays an important role in the DNA repair process by cutting the damaged DNA at the 3′ terminus. Previous studies have indicated some polymorphisms in the XPG gene are associated with stomach cancer susceptibility. We performed this hospital‐based case–control study to evaluate the association of four potentially functional XPG polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C and rs873601G>A) with stomach cancer susceptibility. The four single nucleotide polymorphisms (SNPs) were genotyped in 692 stomach cancer cases and 771 healthy controls. Logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association of interest. Of the studied SNPs, XPG rs873601G>A polymorphism was found to significantly associate with stomach cancer susceptibility (AA versus GG/AG: OR = 1.31, 95% CI = 1.03–1.66, P = 0.027). Combined analysis of all SNPs revealed that the individuals with two of risk genotypes had a significantly increased stomach cancer risk (OR = 1.52, 95% CI = 1.13–2.06). In the stratification analysis, the association between the rs873601AA genotype and stomach cancer risk was observed in older group (>59 year), as well as patients with non‐cardia stomach cancer. Further combined analysis indicated men, smokers, or non‐drinkers more than one risk genotypes had a significantly increased stomach cancer risk. Our results indicate that XPG rs873601G>A polymorphism may be associated with the risk of stomach cancer. Further prospective studies with different ethnicities and large sample sizes are needed to validate our findings.

XPG Gene Polymorphisms Contribute to Colorectal Cancer Susceptibility: A Two-Stage Case-Control Study.

Previous studies have reported that xeroderma pigmentosum group G (XPG) gene polymorphisms may modulate colorectal cancer (CRC) susceptibility. In this study, we performed a two-stage case-control study to comprehensively investigate the associations of five polymorphisms in the XPG gene with CRC risk in 1,901 cases and 1,976 controls from Southern China, including rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601 G>A. After combining data from two stages, we found that three of the studied polymorphisms (rs2094258 C>T, rs751402 C>T, and rs873601 G>A) were significantly associated with CRC susceptibility. After adjustment for age and gender, multivariate logistic regression analysis indicated that carriers of the rs2094258 T alleles had an increased CRC risk [CT vs. CC: adjusted odds ratio (OR)=1.17, 95% confidence interval (CI)=1.01-1.36; TT vs. CC: adjusted OR=1.49, 95% CI=1.18-1.89; TT vs. CT/CC: adjusted OR=1.38, 95% CI=1.10-1.72]. Likely, rs873601 A allele also conferred increased CRC susceptibility. In contrast, a protective association was identified between rs751402 C>T polymorphism and the risk of CRC. In summary, our results indicated that these three polymorphisms were found to associate with CRC susceptibility in a Southern Chinese population.

Polymorphisms in the XPG gene and risk of gastric cancer in Chinese populations

DNA repair genes play an important role in maintaining stability and integrity of genomic DNA. Polymorphisms in nucleotide excision repair genes may cause variations in DNA repair capacity phenotype and thus contribute to cancer risk. In this case-control study of 1,125 gastric cancer cases and 1,196 cancer-free controls, we investigated the association between three functional single nucleotide polymorphisms (SNPs, rs2296147T > C, rs2094258C > T and rs873601G > A) in the xeroderma pigmentosum group G (XPG) gene and gastric cancer risk. We used the Taqman assays to genotype these three SNPs and logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found that only the rs873601A variant genotypes were associated with a significant higher risk for gastric adenocarcinoma (adjusted OR = 1.30, 95% CI = 1.03-1.64 for AA vs. GG and adjusted OR = 1.23, 95% CI = 1.01-1.49 for AA vs. GG/AG). Stratification analysis indicated that this risk was more pronounced in subgroups of older age (>59 years), males, ever-smokers, and patients with NGCA. All these were not found for the other two SNPs (rs2296147T > C and rs2094258C > T). We then performed expression analysis using gastric cancer adjacent normal tissues from 141 patients and found that the A variant allele was associated with non-significantly reduced expression of XPG mRNA (P(trend) = 0.107). Further analysis using mRNA expression data from the HapMap suggested that the A allele was associated with significantly reduced expression of XPG mRNA in normal cell lines for 45 Chinese (P(trend) = 0.003) as well as for 261 subjects with different ethnicities (P(trend) = 0.001). These support the hypothesis that functional XPG variants may contribute to the risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings.

Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: A retrospective multicentric study

Aim Trabectedin sensitivity is increased in cells with functional nucleotide excision DNA repair, whereas efficient homologous recombination repair leads to resistance. On this basis, a retrospective study of mRNA expression of BRCA1 (breast cancer susceptibility 1 gene), XPG ( Xeroderma pigmentosum group G gene) and ERCC1 (excision-repair cross complementing group 1 gene) in tumour samples from sarcoma patients treated with trabectedin was conducted, to correlate DNA repair profiles with patient outcome. Materials and methods Quantification of expression in paraffin embedded tumour samples from 245 patients with advanced sarcomas was performed by qRT-PCR (quantitative real-time polymerase chain reaction). Median values were used as cut-off to define low/high mRNA expression. Results Low BRCA1 mRNA expression in tumour samples correlated with statistically significant better response to trabectedin. In contrast to other DNA interacting agents, high expression of XPG was significantly correlated with increased response to the drug and high ERCC1 or XPD ( Xeroderma pigmentosum group D gene) expression did not have a detrimental impact. A composite signature including low BRCA1 and high ERCC1 and/or XPG identifies a highly sensitive population of sarcomas with significantly improved treatment outcome. Discussion This retrospective study indicates that the DNA repair profile predicts improved outcomes in advanced sarcoma patients when treated with trabectedin. This clinical utility of this signature should be evaluated in prospective enriching studies in sarcoma and other malignancies for patients sensitive to trabectedin.

Relationship between XPG codon 1104 polymorphism and risk of primary lung cancer.

DNA repair plays a critical role in protecting the genome from insults of cancer-causing agents, such as those found in tobacco smoke. Therefore, reduced DNA repair capacity can increase the susceptibility to smoking-related cancers. Recently, several polymorphisms have been identified in the xeroderma pigmentosum group G (XPG) gene, and it is possible that these polymorphisms may affect the DNA repair capacity, thereby modulating cancer susceptibility. We investigated the relationship between the His1104Asp polymorphism in the XPG gene and the risk of lung cancer. The study population consisted of 310 lung cancer patients and 311 healthy controls who were frequency (1:1) matched based on age and sex. The Asp/Asp genotype was more frequent in the controls (28.9%) than in the cases (18.7%) and associated with a significantly decreased risk of lung cancer [adjusted odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.37-0.80] when the combined His/His and His/Asp genotype was used as the reference. The protective effect of the Asp/Asp genotype against lung cancer was statistically significant in the older subjects (adjusted OR = 0.51, 95% CI = 0.37-0.80), males (adjusted OR = 0.54, 95% CI = 0.35-0.83), and lighter smokers (adjusted OR = 0.48, 95% CI = 0.25-0.94) in a stratification analysis. When the lung cancers were analyzed by histologic type, the Asp/Asp genotype was associated with a significantly decreased risk of squamous cell carcinoma (adjusted OR = 0.55, 95% CI = 0.34-0.88) and small cell lung cancer (adjusted OR = 0.44, 95% CI = 0.20-0.97), but non-significant decreased risk of adenocarcinoma (adjusted OR = 0.64, 95% CI = 0.36-1.12). These results suggest that the XPG codon 1104 polymorphism contributes to genetic susceptibility to lung cancer.

Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene.

The xeroderma pigmentosum group G (XP-G) gene (XPG) encodes a structure-specific DNA endonuclease that functions in nucleotide excision repair (NER). XP-G patients show various symptoms, ranging from mild cutaneous abnormalities to severe dermatological impairments. In some cases, patients exhibit growth failure and life-shortening and neurological dysfunctions, which are characteristics of Cockayne syndrome (CS). The known XPG protein function as the 3' nuclease in NER, however, cannot explain the development of CS in certain XP-G patients. To gain an insight into the functions of the XPG protein, we have generated and examined mice lacking xpg (the mouse counterpart of the human XPG gene) alleles. The xpg-deficient mice exhibited postnatal growth failure and underwent premature death. Since XPA-deficient mice, which are totally defective in NER, do not show such symptoms, our data indicate that XPG performs an additional function(s) besides its role in NER. Our in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the early onset of immortalization and accumulation of p53.