Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochrome P450 1A1 (CYP1A1) activity is associated with increased susceptibility to lung cancer induced by polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BP). In non-hepatic human tissues, CYP1A1 is the principal enzyme responsible for the metabolic activation of the proximate BP mutagenic metabolite, (-)-benzo[a]pyrene-trans-7,8-dihydrodiol, to (+)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide, the ultimate BP mutagen. We have genetically engineered both DNA repair-deficient (xeroderma pigmentosum group A) and DNA repair-proficient human skin fibroblasts to express human CYP1A1 under control of the inducible mouse metallothionein-I promoter. CYP1A1 activity was induced by CdSO4 and monitored by following the O-deethylation of ethoxy fluorescein ethyl ester or of 7-ethoxyresorufin. Induced CYP1A1 activities were similar in both cell lines and were dependent on CdSO4 concentration and induction time. Maximal CYP1A1 activities were obtained in 4-6 h with 5-7 microM CdSO4. BPD-induced cytotoxicity and hypoxanthine phosphoribosyl transferase mutagenicity were both quantitatively correlated with the level of CYP1A1 activity and were greater in DNA repair-deficient cells than in DNA repair-proficient cells. The results suggest that modestly induced CYP1A1 activity is a risk factor in polycyclic aromatic hydrocarbon-induced carcinogenesis.
 ...
PMID:Cytotoxicity and genotoxicity of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol in CYP1A1-expressing human fibroblasts quantitatively correlate with CYP1A1 expression level. 792 75

The observation of cancer in an individual does not identify the causative agent(s). However, epidemiological data on populations do indicate that a large fraction of human cancers are associated with lifestyle/diet. Such studies may also help identify the etiologic agents but unless there are good dose-response data for humans and/or animal models, the probability of identifying the agent is not high. Cancers may result from endogenous reactions, such as oxidations or from exogenous agents, such as tobacco smoke (lung cancer), sunlight exposure (skin cancer), aflatoxin (liver cancer), and relatively high doses of ionizing radiations (many types of cancers). Many carcinogenic chemicals have been identified in the workplace but, they usually do not affect the overall population. Most cancer causing agents affect cellular DNA and change its coding specificity and act as cancer initiators. The repair of DNA damage ameliorates most of these endogenous and exogenous changes. The important role of DNA repair in controlling the induction of human cancer came from the observation that individuals with the skin cancer-susceptible, human disease xeroderma pigmentosum (XP) were defective in nucleotide excision repair. Endogenous DNA damages are usually damages to individual bases and are usually repaired by systems of glycosylases and endonucleases. It should be useful to investigate the rates of appearance of tumors in normal mice and in mice knocked out for specific repair enzymes because such mice could be used to test the roles of diet and caloric input in affecting particular types of endogenous damages.
 ...
PMID:Human cancer: etiologic agents/dose responses/DNA repair/cellular and animal models. 1137 81

The DNA repair protein xeroderma pigmentosum complementation group D (XPD) is involved in the nucleotide excision repair of DNA lesions induced by many tobacco and environmental carcinogens. In order to study the functional impact of the common polymorphisms in XPD exon 10 (G > A, Asp312Asn) and exon 23 (A > C, Lys751Gln), we have genotyped 185 Swedish lung cancer cases (97 smokers and 88 never-smokers) and 162 matched population controls (83 smokers and 79 never-smokers). Presence of one or two variant alleles was associated with increased risk for lung cancer among never-smokers only, in particular younger (<70 years) never-smokers [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.1-6.5 for exon 10; OR = 3.2, 95% CI = 1.3-8.0 for exon 23, adjusted for age, gender and environmental tobacco smoke]. Aromatic DNA adduct level (AL) in peripheral lymphocytes was found to be similar between cases and controls, but significantly increased by current or recent smoking. Overall, there was a significant trend for increasing AL with increasing number of variant alleles in exon 10 (P = 0.02) or in exon 23 (P = 0.001). In addition, subjects with the combined exon 10 AA and exon 23 CC genotype showed a significantly higher AL compared with all those with any of the other genotypes (P = 0.02). We conclude that the XPD variant alleles may be associated with reduced repair of aromatic DNA adducts in general and increased lung cancer risk among never-smokers.
 ...
PMID:The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. 1196 Sep 12

X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) are mainly involved in base excision repair (BER) and nucleotide excision repair (NER) of DNA repair pathways, respectively. Polymorphisms of DNA repair gene XRCC1 and XPD has recently been identified, and there is a growing body of evidence that these polymorphisms may have some phenotypic significance. To investigate the role of XRCC1 polymorphisms (codon 194 and codon 399) and XPD polymorphism (codon 751) in lung cancer, a population-based case-control study of 109 lung cancer patients and 109 healthy control subjects (individually matched on age and gender) in a Chinese population was conducted. XRCC1 and XPD genotypes were identified using PCR-restriction fragments length polymorphism technique. Conditional logistic regression analysis revealed that XRCC1 codon 194Trp/Trp genotype was associated with a borderline increased risk of lung cancer [adjusted odd ratio (OR) = 3.06; confidence interval (CI) 0.94-9.92]. The XPD 751 Lys allele (combined Lys/Lys and Lys/Gln genotypes) was associated with a significantly increased risk of lung cancer (OR = 3.19; CI 1.01-10.07). The risk of lung cancer increased more than additive interaction (adjusted OR = 8.77; CI 1.47-52.31) for the individuals with both putative high-risk genotypes of XRCC1 194 Trp/Trp and XPD 751 Lys allele. Our results suggested that the genotypes of XRCC1 194Trp/Trp and XPD 751 Lys allele might be the risk genotypes for lung cancer in Chinese population.
 ...
PMID:DNA repair gene XRCC1 and XPD polymorphisms and risk of lung cancer in a Chinese population. 1215 50

Associations between lung cancer risk and common polymorphisms in the DNA repair genes xeroderma pigmentosum complementation group D (XPD), X-ray repair cross-complementing group 1 (XRCC1), XRCC3 and apurinic/apyrimidinic endonuclease/redox factor 1 were examined within a randomized clinical trial designed to determine whether alpha-tocopherol, beta-carotene, or both would reduce cancer incidence among male smokers in Finland. We found no direct association between lung cancer risk and any of the DNA repair genotypes studied, however, the association between XPD codon 751 genotype and lung cancer was modified by alpha-tocopherol supplementation, and the association between XRCC1 codon 399 genotype and lung cancer was modified by the amount of smoking. Our results suggest that common alterations in single DNA repair genes are not major determinants of lung cancer susceptibility among smokers.
 ...
PMID:Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland. 1261 30

Lung cancer, a disease related mostly to tobacco smoke exposure and a leading cause of cancer-related death in industrialized countries, is frequently associated with mutations in the p53 tumor suppressor gene. Genetic differences resulting in inter-individual variation in DNA repair capacity may in part account for susceptibility of a cell to genotoxic agents leading to somatic mutations, including p53 mutations, and eventual transformation of a normal cell into a malignant phenotype. The objective of this study is to investigate the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399), and p53 mutations among lung cancer patients. Lung tumors from 204 smokers with non-small cell lung cancer (NSCLC) were analyzed for mutations in exons 5-8 of the p53 gene and genotypes of XPD and XRCC1. p53 mutations were found in 20% (40/204) of the patients. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations (13.8%) than XPD 312 Asp/Asp (27.3%) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20-0.89, P = 0.023]. No association was found between p53 mutations and either XPD Lys751Gln or XRCC1 Arg399Gln. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test). These results suggest that individuals who smoke and have the XPD codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in deficient DNA repair.
 ...
PMID:Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer. 1284 88

Cisplatin or carboplatin is commonly used with gemcitabine, docetaxel, paclitaxel, or vinorelbine as chemotherapy doublets in the treatment of advanced non-small-cell lung cancer (NSCLC). Several randomized trials have failed to identify major differences in survival between any of these doublets. This lack of evidence for improvement in survival with any chemotherapy regimen has created a tabula rasa where no more large randomized trials should be conducted without including a genetic analysis. Patients see survival as their major concern, and other considerations, such as cost and quality of life, are relegated to lower positions. Genetic alterations related to the transcription-coupled repair pathway of the nucleotide excision repair system (TC-NER) have revealed the subset of patients who are resistant to cisplatin. TC-NER involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. For a long time, ERCC1 mRNA levels have been known to correlate with DNA repair capacity in various tissues. Levels of DNA cisplatin adducts in peripheral blood and buccal mucosa cells predict chemotherapy response, and high ERCC1 mRNA levels have been related to chemoresistance in ovarian cancer and in malignant lymphocytes from chronic lymphocytic leukemia. Moreover, in some instances, mRNA expression has been correlated with polymorphisms. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated NSCLC patients. An ongoing customized ERCC1-based chemotherapy trial has been designed based on this knowledge. Patients are randomized to the control arm of cisplatin/docetaxel or to the experimental arm, where docetaxel is combined with cisplatin or gemcitabine according to ERCC1 levels. To date, 86 patients have been included.
Lung Cancer 2003 Aug
PMID:Genetic testing for chemotherapy in non-small cell lung cancer. 1286 68

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.
 ...
PMID:Relationship between XPG codon 1104 polymorphism and risk of primary lung cancer. 1286 23

Only about one third of non-small-cell lung cancer (NSCLC) patients respond to cisplatin-based chemotherapy. Cisplatin DNA adducts are commonly repaired through the nucleotide excision repair pathway. The study of rare inherited disorders such as xeroderma pigmentosum and Cockayne syndrome has disclosed that XP genes, including XPD, play an essential role in DNA repair, both in the global genomic repair and in the transcription-coupled repair pathways. XPD polymorphism and decreased expression of XP genes have both been linked to lower DNA repair capacity. ERCC1 overexpression has been associated with cisplatin resistance, and experimental evidence shows a close association between ERCC1 and XPD. In the present study, we have examined XPD polymorphisms at codons 751 and 312 in DNA isolated from peripheral blood in 39 patients with gemcitabine/cisplatin-treated locally advanced non-small-cell lung cancer Although no significant correlation was observed between XPD genotype and objective response, a trend toward better response was observed in patients with XPD polymorphism at codon 312. The map of the nucleotide excision repair pathway can be used to design translational research studies to identify and validate predictive markers of response to cisplatin, and the Spanish Lung Cancer Group has recently accrued 250 gemcitabine/cisplatin-treated NSCLC patients for a prospective assessment of XPD genotype
Clin Lung Cancer 2003 Jan
PMID:Assessment of nucleotide excision repair XPD polymorphisms in the peripheral blood of gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients. 1462 13

Reduced DNA repair capacity due to inherited polymorphisms may increase the susceptibility to smoking-related cancers. In this report, we investigate the relationship between xeroderma pigmentosum complementary group C poly (AT) insertion/deletion polymorphism (XPC-PAT) of the XPC gene and lung cancer risk in a hospital-based case-control study of 359 newly diagnosed lung cancer patients and 375 control subjects matched on age, sex, and catchment area. The XPC genotype was determined by PCR-RFLP, and the results were analyzed using logistic regression, adjusting for relevant covariates. We found that the frequency of the PAT+/+ genotype was higher in the cases (20.6%) than in the controls (14.1%; P = 0.057) and that the PAT+/+ subjects were at significantly increased risk for lung cancer [adjusted odds ratio (OR), 1.60; 95% confidence interval (95% CI), 1.01-2.55]. Stratified analysis revealed that the risk was higher in former smokers (OR, 2.15; 95% CI, 1.07-4.31) and older people (OR, 2.76; 95% CI, 1.02-7.51), although this probably occurs due to 63.4% of cases older than 73 years being ex-smokers. When stratified by histologic type, the variant genotype was associated with statistically significant increased risk for squamous cell carcinoma (OR, 1.93; 95% CI, 1.06-3.51). In conclusion, our findings support the hypothesis that PAT and intron 11 C/A XPC polymorphisms are linked in the Spanish population and may contribute to the risk of developing lung cancer probably due to a higher frequency of deletion of exon 12 and reduced DNA repair capacity of the XPC protein.
 ...
PMID:Poly (AT) polymorphism in intron 11 of the XPC DNA repair gene enhances the risk of lung cancer. 1553 8


1 2 3 4 Next >>