Biomedical subjects

Xifeng Wu

Publications and source records attributed to Xifeng Wu.

At least 37 records · Page 2Linked to original sources

PubMed2006

Association between glutathione S-transferase pi polymorphisms and survival in patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: Glutathione S-transferase (GST) pi (GSTP1) is a detoxification enzyme with substrate specificity for both exogenous carcinogens and chemotherapy agents. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, the authors reported that the exon 6 variant was associated with an increased risk of lung carcinoma, particularly among men, younger patients, and ever smokers. In this study, the authors hypothesized that variant GSTP1 genotype would result in reduced inactivation of chemotherapy agents and improved survival in patients with advanced-stage nonsmall cell lung carcinoma (NSCLC), a population that is likely to receive platinum-based chemotherapy. METHODS: Patients with Stage III and IV NSCLC who were enrolled in a molecular epidemiology study were identified, and a polymerase chain reaction-restriction fragment length polymorphism assay was used to genotype GSTP1 exons 5 and 6 in 424 patients and 425 patients, respectively. RESULTS: Patients who had the exon 6 variant genotype (Ala/Val or Val/Val) had significantly better survival compared with patients who had the wild type genotype (Ala/Ala; P = 0.037), with median survival of 16.1 months and 11.4 months, respectively. Multivariate analysis revealed a reduced adjusted hazard ratio (HR) of death associated with the exon 6 variant genotype of 0.75 (95% confidence interval [95% CI], 0.54-1.05). This protective association was observed in younger patients (younger than age 62 yrs; HR, 0.59; 95% CI, 0.57-0.97) and in males (HR, 0.64; 95% CI, 0.41-0.99). GSTP1 exon 5 genotype was not associated with survival. CONCLUSIONS: GSTP1 exon 6 variant genotypes may be associated with improved survival among patients with Stage III and IV NSCLC.

Aged↗

PubMed2006

Combined effects of the p53 and p73 polymorphisms on lung cancer risk.

Lung cancer is a multigenic disease where one variant single nucleotide polymorphism may have only a modest independent effect on the disease phenotype, yet in aggregate, multiple biologically relevant single nucleotide polymorphisms may provide a more accurate representation of risk. Polymorphisms in members of the p53 family, such as p53 and p73, that have a functional relevance would be predicted to contribute to the disease phenotype. In this analysis, we used genotype data from 863 lung cancer cases and 852 healthy controls to test for multigenetic effects of polymorphisms at p53 exon 4, introns 3 and 6, and at p73 exon 2. All individuals in this analysis were self-reported non-Hispanic Caucasians. When the p73 and p53 variant alleles were combined and analyzed as a continuous variable, there was a 13% increase [odds ratios (OR), 1.13; 95% confidence intervals (CI), 1.05-1.21] in lung cancer risk for each additional variant allele. Furthermore, when the number of variant alleles was categorized into three groups (zero, one to three, and four or more variants), there was evidence of a gene-dosage effect with increased risks for individuals with one to three variants (OR, 1.30; 95% CI, 1.05-1.61) and four or more variants (OR, 1.78; 95% CI, 1.23-2.56). When the data were stratified by smoking status, an increased risk for lung cancer was evident only in current (OR, 2.32; 95% CI, 1.25-4.33) and former smokers (OR, 1.73; 95% CI, 1.02-2.94) with four or more variants. Younger individuals with four or more variants were also at a significantly increased risk for lung cancer (OR, 3.15; 95% CI, 1.62-6.12). This study provides support for the multigenetic effects of variant alleles from p53 exon 4, and introns 3 and 6, and p73, and their interplay with smoking, resulting in a significantly increased risk for lung cancer in this Caucasian population.

Aged↗

PubMed2006

Personal permanent hair dye use is not associated with bladder cancer risk: evidence from a case-control study.

Whether personal hair dye use is associated with an increased bladder cancer risk has been controversial and there are limited available data addressing this issue. We used a large case-control study of 712 incident bladder cancer cases and 712 age-, gender-, and ethnicity-matched controls to evaluate this association. After adjusting for confounding variables, the use of permanent hair dye was not associated with bladder cancer risk in all subjects [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.50-1.30], in women (OR, 0.90; 95% CI, 0.41-1.96), or in men (OR, 0.68; 95% CI, 0.36-1.29). The lack of association was not modified by duration of use, frequency of use, lifetime use, age at first use, or color of use in subsequent stratified analyses. Our data do not support personal hair dye use as an important risk factor for bladder cancer.

Adult↗

PubMed2006

Mutagen sensitivity and neoplastic progression in patients with Barrett's esophagus: a prospective analysis.

BACKGROUND: Defects in DNA damage recognition and repair have been associated with a wide variety of cancers. We conducted a prospective study to determine whether mutagen sensitivity, as determined by an in vitro assay, was associated with the future development of cancer in patients with Barrett's esophagus, which is associated with increased risk of progression to esophageal adenocarcinoma. METHODS: We measured sensitivity to bleomycin in peripheral blood lymphocytes in a cohort of 220 patients with Barrett's esophagus. We followed these patients for 1,230 person-years (range, 3 months to 10.1 years; median, 6.4 years), using development of cancer and aneuploidy as end points. A subset of these patients was evaluated for inactivation of tumor-suppressor genes CDKN2A/p16 and TP53 [by mutation and loss of heterozygosity (LOH)] in their Barrett's segments at the time of, or before, the bleomycin test, and the patients were stratified by CDKN2A/p16 and TP53 status in an analysis of mutagen sensitivity and progression. RESULTS: Bleomycin-sensitive patients were found to be at significantly greater risk of developing aneuploidy (adjusted hazard ratio, 3.71; 95% confidence interval, 1.44-9.53) and nonsignificantly greater risk of cancer (adjusted hazard ratio, 1.63; 95% confidence interval, 0.71-3.75). Among patients with detectable LOH at the TP53 locus (on chromosome 17p), increasing bleomycin sensitivity was associated with increased risk of developing cancer (P(trend) < 0.001) and aneuploidy (P(trend) = 0.005). CONCLUSIONS: This study supports the hypothesis that sensitivity to mutagens increases the risk of neoplastic progression in persons with Barrett's esophagus, particularly those with 17p LOH including TP53.

Adenocarcinoma↗

PubMed2005

Dietary phytoestrogens and lung cancer risk.

CONTEXT: Despite lung-specific in vitro and in vivo studies that support a chemopreventive role for phytoestrogens, there has been little epidemiologic research focused on dietary intake of phytoestrogens and risk of lung cancer. OBJECTIVE: To examine the relationship between dietary intake of phytoestrogens and risk of lung cancer. DESIGN, SETTING, AND PARTICIPANTS: Ongoing US case-control study of 1674 patients with lung cancer (cases) and 1735 matched healthy controls. From July 1995 through October 2003, participants were personally interviewed with epidemiologic and food frequency questionnaires to collect demographic information and to quantify dietary intake of 12 individual phytoestrogens. MAIN OUTCOME MEASURE: Risk of lung cancer, estimated using unconditional multivariable logistic regression analyses stratified by sex and smoking status and adjusted for established and putative lung cancer risk factors. RESULTS: Reductions in risk of lung cancer tended to increase with each increasing quartile of phytoestrogen intake. The highest quartiles of total phytosterols, isoflavones, lignans, and phytoestrogens were each associated with reductions in risk of lung cancer ranging from 21% for phytosterols (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.64-0.97; P = .03 for trend) to 46% for total phytoestrogens from food sources only (OR, 0.54; 95% CI, 0.42-0.70; P<.001 for trend). Sex-specific effects were also apparent. For men, statistically significant trends for decreasing risk with increasing intake were noted for each phytoestrogen group, with protective effects for the highest quartile of intake ranging from 24% for phytosterols (OR, 0.76; 95% CI, 0.56-1.02; P = .04 for trend) to 44% for isoflavones (OR, 0.56; 95% CI, 0.41-0.76; P<.001 for trend), while in women, significant trends were only present for intake of total phytoestrogens from food sources only, with a 34% (OR, 0.66; 95% CI, 0.46-0.96; P = .01 for trend) protective effect for the highest quartile of intake. The apparent benefits of high phytoestrogen intake were evident in both never and current smokers but less apparent in former smokers. In women, statistically significant joint effects were evident between hormone therapy use and phytoestrogen intake. Specifically, high intake of the lignans enterolactone and enterodiol and use of hormone therapy were associated with a 50% (OR, 0.50; 95% CI, 0.31-0.68; P = .04 for interaction) reduction in risk of lung cancer. CONCLUSIONS: While there are limitations and concerns regarding case-control studies of diet and cancer, these data provide further support for the limited but growing epidemiologic evidence that phytoestrogens are associated with a decrease in risk of lung cancer. Confirmation of these findings is still required in large-scale, hypothesis-driven, prospective studies.

Aged↗

PubMed2005

Polymorphisms in inflammation genes and bladder cancer: from initiation to recurrence, progression, and survival.

PURPOSE: Since chronic inflammation contributes to tumorigenesis, we hypothesized that the risk and clinical outcome of bladder cancer (BC) might be modulated by genetic variations in inflammation genes. METHODS: Using the TaqMan method, we genotyped single nucleotide polymorphisms in interleukin (IL) -6 (-174 G-->C), IL-8 (-251 T-->A), tumor necrosis factor-alpha (TNF-alpha; -308 G-->A), and peroxisome proliferator-activated receptor gamma (PPARG; Pro12Ala), and determined their associations with BC initiation and clinical outcome. RESULTS: We found that the IL-6 variant genotype (C/C) was associated with an increased BC risk (OR, 1.77; 95% CI, 1.25 to 2.51). There were joint effects between the variant IL-6 genotypes and smoking status, and between the variant genotypes of IL-6 and other genes. To assess effect on recurrence, we grouped non-muscle-invasive BC patients according to intravesical Bacillus Calmette-Guerin (BCG) treatment status: no BCG, induction BCG (iBCG), and maintenance BCG (mBCG). In the Cox proportional hazards model, the variant IL-6 genotype was associated with an increased recurrence risk (hazard ratio [HR], 4.60; 95% CI, 1.24 to 17.09) in patients receiving mBCG. The variant PPARG genotype was associated with a reduced recurrence risk (HR, 0.41; 95% CI, 0.20 to 0.86) among untreated patients. In patients with non-muscle-invasive BC, the variant IL-6 genotype was associated with an increased progression risk (HR, 1.88; 95% CI, 0.80 to 4.11). In patients with invasive BC, variant IL-6 was associated with improved 5-year overall and disease-specific survival (HR, 0.43; 95% CI, 0.19 to 0.94 and HR, 0.39; 95% CI, 0.15 to 1.00, respectively). CONCLUSION: Inflammation gene polymorphisms are associated with modified BC risk, treatment response, and survival.

Aged↗

PubMed2005

Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study.

BACKGROUND: Since genetic factors may play an important role in lung cancer development at low dose carcinogen exposure, non-smokers are a good model to study genetic susceptibility and its interaction with environmental factors. MATERIALS AND METHODS: We evaluated the role of the metabolic gene polymorphisms CYP1A1MspI, CYP1A1Ile462Val, GSTM1, and GSTT1 in non-smoker lung cancer patients from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Non-smokers (defined as subjects who never smoked on a regular basis) were selected from the GSEC database. We pooled the raw data from 21 case-control studies for a total of 2764 Caucasians (555 cases and 2209 controls) and 383 Asians (113 cases and 270 controls). Tests of heterogeneity and of inclusion bias were performed. RESULTS: A significant association between lung cancer and CYP1A1Ile462Val polymorphism was observed in Caucasians (adjusted OR=2.04, 95% CI 1.17-3.54). GSTT1 deletion seems to be a risk factor for lung cancer in Caucasian non smokers only when the analysis was restricted to studies including healthy controls (adjusted OR=1.66, 95% CI 1.12-2.46). A protective effect on lung cancer was observed with the combination of CYP1A1 wild type, GSTM1 null, and GSTT1 non-null genotypes. None of the analysed polymorphisms were associated with lung cancer in Asian non-smokers. DISCUSSION: Our analysis confirms previous findings that CYP1A1Ile462Val polymorphism may play a role in lung carcinogenesis in Caucasian non-smokers.

Adenocarcinoma↗

PubMed2005

Increased plasma levels of angiogenin and the risk of bladder carcinoma: from initiation ot recurrence.

BACKGROUND: Angiogenesis is a well known prerequisite for tumor growth and metastasis. It is believed that angiogenin initiates cell migration and aids cell proliferation. Based on this, the authors hypothesized that individuals who had increased plasma levels of angiogenin were at an elevated risk for carcinoma of the urinary bladder. METHODS: In this ongoing case-control study, the authors used an enzyme-linked immunosorbent assay to compare plasma levels of angiogenin in 209 patients with bladder carcinoma and in 208 healthy control participants who were matched according to age (+/- 5 years), gender, and ethnicity. RESULTS: The mean plasma angiogenin concentration was significantly higher in patients compared with controls (343.2 ng/mL vs. 308.0 ng/mL, respectively; P < 0.01). High plasma angiogenin levels were associated with a two-fold increased risk for bladder carcinoma. Moreover, in patients who had superficial bladder carcinoma, plasma angiogenin levels were significantly higher among those who had recurrent disease than in those who were without recurrence (P < 0.01). Similarly, patients who had superficial bladder carcinoma with higher angiogenin levels had a shorter recurrence-free survival than patients who had lower angiogenin levels (P < 0.01). Finally, elevated angiogenin levels were associated with an increased recurrence risk, with hazard ratio of 2.85. CONCLUSIONS: The results of this study demonstrated that the plasma levels of angiogenin were significantly higher in patients who had bladder carcinoma compared with healthy control participants and in patients with superficial bladder carcinoma who had recurrent disease compared with patients who were without recurrence. Therefore, an elevated plasma level of angiogenin may serve as a novel predictor for the risk of bladder carcinoma.

Biomarkers, Tumor↗

PubMed2005

Roles of tumor suppressor and telomere maintenance genes in cancer and aging--an epidemiological study.

Advanced age is strikingly linked to increased incidence of cancer. To gain insight into the mechanism underlying the association between increased cancer incidence and aging in normal human physiological conditions, we used a case-control design and measured the mRNA expression levels of p53, ATM, hTERT and TRF2, the four major protectors of genomic integrity, in isolated peripheral blood lymphocytes from 202 confirmed bladder cancer (BC) patients and 199 healthy controls. Significant age effects on expression levels were observed. When we divided the study subjects into three age groups (<57, 57-65 and > or = 65), the expressions of p53, ATM and TRF2 significantly decreased with advancing age in cases (P for trend < or = 0.001, 0.01 and 0.01 for p53, ATM and TRF2, respectively). In controls, however, p53 expression significantly increased with advancing age (P for trend = 0.05). Among subjects > or = 65 years of age, the expressions of p53, ATM and TRF2 were significantly lower in cases than in controls (P = 0.003, 0.04 and 0.05 for p53, ATM and TRF2, respectively), suggesting that attenuated genomic maintenance mechanisms lead to increased cancer risk in older individuals. When we dichotomized our study population at the median age of study subjects (61 years old), low p53 expression was associated with a significantly increased BC risk in older people (OR = 2.27, 95% CI = 1.00-5.16). In addition, older subjects without detectable hTERT expression had a significantly reduced BC risk (OR = 0.41, 95% CI = 0.17-0.99). Our study provides the first epidemiologic evidence that the increased genomic instability resulting from the combination of telomere dysfunction, impaired ATM- and p53-mediated DNA damage, and/or telomere dysfunction response pathway contributes to increased cancer incidence in the elderly population.

Aged↗

PubMed2005

High mutagen sensitivity in peripheral blood lymphocytes predicts poor overall and disease-specific survival in patients with stage III non-small cell lung cancer treated with radiotherapy and chemotherapy.

PURPOSE: To investigate whether the bleomycin sensitivity assay, an in vitro peripheral blood lymphocyte assay, can predict outcome in patients with inoperable stage III non-small-cell lung cancer (NSCLC) treated with definitive radiotherapy and chemotherapy. EXPERIMENTAL DESIGN: We identified 102 patients with inoperable stage III NSCLC cell lung cancer treated with definitive radiotherapy and chemotherapy. The patients' pretreatment peripheral blood lymphocyte cultures were treated with the radiomimetic mutagen bleomycin. An index of bleomycin sensitivity was determined by counting the number of chromatid breaks in 50 metaphases. The correlation between bleomycin sensitivity (expressed as mean breaks per cell) and clinical outcome was analyzed. RESULTS: High bleomycin sensitivity (defined as a mean of >1.02 chromatid breaks/cell, representing the third quartile of bleomycin sensitivity) predicted poor disease-specific survival and overall survival. The 6-year disease-specific survival was 27% in patients with high bleomycin sensitivity compared with 46% in patients without such sensitivity (P = 0.0094). The association remained statistically significant when adjusted for smoking status, age, and radiation dose. The 6-year overall survival was 19% for patients with high bleomycin sensitivity and 29% for those without (P = 0.0193). There was a trend toward worse local regional control and worse disease-free survival among patients with high bleomycin sensitivity. There was no difference between the two groups in distant metastasis-free survival or radiation treatment-related complications. CONCLUSIONS: High bleomycin sensitivity correlated with poor overall survival and disease-specific survival in these patients with stage III NSCLC treated with radiotherapy and chemotherapy. Bleomycin sensitivity may function as a biomarker for poor clinical outcome for this group of patients.

Aged↗

PubMed2005

An association between a NQO1 genetic polymorphism and risk of lung cancer.

NAD(P)H:quinone oxidoreductase (NQO1) is a detoxification enzyme that protects against the regeneration of reactive oxygen species chemically induced by oxidative stress, cytotoxicity, mutagenicity, and carcinogenicity. The protection conferred by NQO1 protein reduces certain environmental carcinogens, such as nitroaromatic compounds, heterocyclic amines, and possible cigarette smoke condensate. The gene coding for NQO1 has a genetic polymorphism (C-->T) at nucleotide position 609 (i.e. amino acid codon 187) of the NQO1 cDNA. This polymorphism was shown to reduce NQO1 enzyme activity, thereby diminishing the protection provided by NQO1. Therefore, we hypothesized that individuals with the variant NQO1 genotype are at higher risk for lung cancer. Using a case-control study, we genotyped the NQO1 variants successfully by PCR-RFLP in 826 lung cancer patients and 826 healthy control subjects matched for age, sex, ethnicity, and smoking status. The frequency of the NQO1 T-allele was statistically significantly different among three ethnic groups (p<0.001). In further analysis of Caucasians, the variant NQO1 genotypes (CT and TT) were associated with a marginally increased lung cancer risk (OR=1.19; 95% CI: 0.95-1.50). The elevated lung cancer risk was only evident in younger individuals (age <62 years old) (OR=1.46; 95% CI: 1.04-2.05), women (OR=1.89; 95% CI: 1.33-2.68), and never smokers (OR=1.80; 95% CI: 1.03-3.13). Furthermore, we found a statistically significant trend in the development of lung cancer at an early age in women with increasing copies of the variant allele (p=0.03). These results suggest that the NQO1 variant genotype may modulate lung cancer risk, especially in younger individuals (age<62), women, and never smokers.

Base Sequence↗

PubMed2005

Opposing effects of emphysema, hay fever, and select genetic variants on lung cancer risk.

The authors compared histories of nonmalignant respiratory diseases (asthma, bronchitis, emphysema, hay fever, and pneumonia) in 1,553 lung cancer patients and 1,375 healthy controls enrolled in a Texas case-control study from 1995 to 2003. They incorporated data on two biologically relevant polymorphic genes, matrix metalloproteinase-1 and myeloperoxidase. Emphysema was associated with a statistically significant increased lung cancer risk (odds ratio (OR) = 2.87, 95% confidence interval (CI): 2.20, 3.76), while hay fever had a significant protective effect (OR = 0.58, 95% CI: 0.48, 0.70). Odds ratios were consistent after exclusion of respiratory disease diagnoses made up to 10 years before interview. There was little association between other respiratory diseases and lung cancer risk. Among carriers of "protective" genotypes, emphysema was associated with a 1.7-fold increased risk (95% CI: 0.84, 3.50), as compared with the substantially higher risk for persons possessing one (OR = 4.98, 95% CI: 2.94, 8.44) or two (OR = 4.23, 95% CI: 1.84, 9.73) "adverse" genotypes. For hay fever, significantly decreased risks were evident with one (OR = 0.32, 95% CI: 0.21, 0.50) or two (OR = 0.35, 95% CI: 0.19, 0.66) protective genotypes as compared with none (OR = 0.69, 95% CI: 0.30, 1.59). The biologic role of respiratory disease in lung cancer is unclear. Further study may yield new insights for identification of susceptible subgroups.

Asthma↗

PubMed2005

Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer.

PURPOSE: Interindividual differences in DNA repair capacity not only modify individual susceptibility to carcinogenesis, but also affect individual response to cancer treatment. Nucleotide excision repair (NER) is one of the major DNA repair pathways in mammalian cells involved in the removal of a wide variety of DNA lesions. Polymorphisms in NER genes may influence DNA repair capacity and affect clinical outcome of bladder cancer treatment. EXPERIMENTAL DESIGN: To test the influence of NER gene polymorphisms on superficial bladder cancer outcome (recurrence and progression), we conducted a follow-up study of 288 patients with superficial bladder cancer. Median follow-up among patients who were recurrence-free at the end of observation was 21.7 months from diagnosis. The specific polymorphic loci examined include XPA [A/G at 5' untranslated region (UTR)], XPC (poly AT, Ala(499)Val, Lys(939)Gln), XPD (Asp(312)Asn, Lys(751)Gln), XPG (His(1104)Asp), ERCC 1 (G/T at 3' UTR), and ERCC6 (Met(1097)Val, Arg(1230)Pro). RESULTS: The ERCC6 (Met(1097)Val) polymorphism had a significant impact on recurrence: carriers of at least one variant allele (Val) had a significantly higher recurrence risk than carriers of the wild-type allele (Met/Met; hazard ratio, 1.54; 95% confidence interval, 1.02-2.33). There were no overall statistically significant differences in the distributions of the other polymorphisms between patients with and without recurrence. However, when we combined these variant genotypes, there was a significant trend for an increased recurrence risk with an increasing number of putative high-risk alleles. Using individuals with five or fewer putative high-risk alleles as the reference group, individuals with six to seven risk alleles and individuals with eight or more risk alleles had higher recurrence risks, with hazard ratios of 0.92 (0.54-1.57) and 2.53 (1.48-4.30), respectively (P for trend < 0.001). There was also a significant trend for shorter recurrence-free survival time with increasing number of variant alleles (log rank test, P = 0.0007). When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively). There were no significant individual or joint associations between these polymorphisms and progression. CONCLUSIONS: These data suggest that interindividual differences in DNA repair capacity may have an important impact on superficial bladder cancer recurrence. A pathway-based approach is preferred to study the effects of individual polymorphism on clinical outcomes.

Aged↗

PubMed2005

Integrative epidemiology: from risk assessment to outcome prediction.

In this paper, we advance the concept of integrative epidemiology. Our unifying premise is that the same genes that are implicated in cancer risk may also be involved in a person's propensity to carcinogenic exposure and/or to modulation of therapeutic outcome. In the coming years, molecular epidemiology will play an increasingly prominent role in early detection of cancer and in identifying genetically high-risk subgroups that might benefit disproportionately from more intensive screening or chemoprevention interventions. Molecular epidemiology is also integral to pharmacogenetic research, by constructing genetic profiles that could be used to individualize therapy and to understand the functional consequences of chemoprevention, chemotherapy, or radiotherapy response. At the level of risk assessment, the focus might be on germline polymorphisms in candidate genes; for early detection, epigenetic events in these same or other genes may be relevant; and tumor tissue expression levels, loss of heterozygosity, genomic amplification, rearrangements, or somatic mutations in the same classes of genes may determine outcome. We will provide examples of how changes in the function of a single gene can contribute to susceptibility to carcinogenic exposure, predisposition to cancer development, patient prognosis, and prediction of outcome.

Carcinogens↗

PubMed2005

Cell cycle checkpoints, DNA damage/repair, and lung cancer risk.

Given that defects in cell cycle control and DNA repair capacity may contribute to tumorigenesis, we hypothesized that patients with lung cancer would be more likely than healthy controls to exhibit deficiencies in cell cycle checkpoints and/or DNA repair capacity as gauged by cellular response to in vitro carcinogen exposure. In an ongoing case-control study of 155 patients with newly diagnosed lung cancer and 153 healthy controls, we used the comet assay to investigate the roles of cell cycle checkpoints and DNA damage/repair capability in lung tumorigenesis. The median gamma-radiation-induced and benzo(a)pyrene diol epoxide-induced Olive tail moments, the comet assay parameter for measuring DNA damage, were significantly higher in the case group (5.31 and 4.22, respectively) than in the control group (4.42 and 2.83, respectively; P < 0.001). Higher tail moments of gamma-radiation and benzo(a)pyrene diol epoxide-induced comets were significantly associated with 2.32- and 4.49-fold elevated risks, respectively, of lung cancer. The median gamma-radiation-induced increases of cells in the S and G(2) phases were significantly lower in cases (22.2% and 12.2%, respectively) than in controls (31.1% and 14.9%, respectively; P < 0.001). Shorter durations of the S and G(2) phases resulted in 4.54- and 1.85-fold increased risks, respectively, of lung cancer. Also observed were joint effects between gamma-radiation-induced increases of S and G(2) phase frequencies and mutagen-induced comets. In addition, we found that in controls, the S phase decreased as tail moment increased. This study is significant because it provides the first molecular epidemiologic evidence linking defects in cell cycle checkpoints and DNA damage/repair capacity to elevated lung cancer risk.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed2005

Predictors of esophageal cancer risk: assessment of susceptibility to DNA damage using comet assay.

Individuals' susceptibility to DNA damage could be identified by mutagen-challenged assays. We tested the hypothesis that susceptibility to DNA damage, measured by comet assay, may be associated with increased esophageal cancer (EC) risk. We recruited 102 subjects with previously untreated EC and 112 healthy controls. Baseline (untreated), benzo[a]pyrene diol epoxide (BPDE)-induced, and gamma-radiation-induced DNA damage were quantified by the Olive tail moment parameter. The mean tail moment was significantly higher in cases than in controls at baseline (case vs. control: 2.6 vs. 1.9, P < 0.01), after BPDE induction (case vs. control: 3.8 vs. 2.7, P < 0.01), and after gamma-radiation-induction (case vs. control: 5.0 vs. 3.8, P < 0.01). When data were dichotomized with the median values in the controls, a significantly increased risk for EC was observed for high baseline tail moment [odds ratio (OR) = 5.7, 95% confidence interval (CI) = 2.9-11.4], high BPDE-induced tail moment (OR = 5.8, 95% CI = 2.9-11.8), and high gamma-radiation-induced tail moment (OR = 4.6, 95% CI = 2.4-8.8). Further, the association between DNA damage and EC was stronger in never smokers than in ever smokers. Compared with subjects not sensitive to both mutagens, individuals sensitive to only one mutagen showed a 3.4-fold risk for EC and those sensitive to both mutagens showed an 8.7-fold risk for EC. Thus, we conclude that susceptibility to DNA damage as assessed by comet assay might help identify individuals with high EC risk.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed2005

Inflammatory gene polymorphisms influence risk of postoperative morbidity after lung resection.

BACKGROUND: Polymorphisms in genes encoding proteins involved in the inflammatory response may lead to a differential response to a noxious stimulus. We hypothesized that proinflammatory alleles at candidate loci would predispose patients undergoing lung resection to cardiopulmonary complications with a presumed inflammatory cause. METHODS: We determined the genotypes at six candidate loci in 155 patients who underwent 160 lung resection operations at our center. We correlated these results with data from our clinical database, constructed a model predicting the risk of postoperative complications, and assessed its adequacy using receiver operating characteristic curve methodology. RESULTS: Preexisting cardiovascular disease (p < 0.001), primary lung cancer (p = 0.009), extent of lung resection (p = 0.042), interleukin 6 genotype (p = 0.017), and tumor necrosis factor genotype (p = 0.005) were significantly associated with complications. The odds ratio for complications for rare allele homozygosity was 3.9 (95% confidence interval, 1.4 to 10.4) for interleukin 6 and 15.3 (95% confidence interval, 1.7 to 131.4) for tumor necrosis factor. In multivariate analysis we found that cardiovascular disease (p < 0.001; odds ratio, 4.0 [95% confidence interval, 1.9 to 8.6]), interleukin 6 genotype (p = 0.027; odds ratio, 1.8 [95% confidence interval, 1.1 to 3.1]), and tumor necrosis factor genotype (p = 0.011; odds ratio, 2.5 [95% confidence interval, 1.2 to 5.1]) were independently predictive of complications, with an area under the receiver operating characteristic curve for the entire model of 0.765. CONCLUSIONS: Carriage of specific alleles, and homozygosity in particular, at loci within the interleukin 6 and tumor necrosis factor genes appears to contribute to the risk of experiencing an adverse event after lung resection.

Aged↗

PubMed2005

Glutathione peroxidase 1 gene polymorphism and risk of recurrence in patients with superficial bladder cancer.

OBJECTIVES: To investigate the potential of genetic polymorphism (Pro198Leu) in the human glutathione peroxidase 1 (hGPX1) gene as a biologic marker predictive of bladder cancer recurrence. Given the high propensity for superficial bladder cancer recurrence, biologic markers that are predictive of recurrence may provide additional helpful information in bladder cancer treatment. To date, few valuable molecular markers have been closely associated with bladder cancer recurrence. METHODS: In this ongoing prospective study, we investigated the potential of genetic polymorphism (Pro198Leu) in the hGPX1 gene, whose protein product is an important metabolic enzyme, as a recurrence predictor. RESULTS: This study included 224 patients with superficial bladder cancer. During a median follow-up of 25.2 months, 138 (61.6%) of the 224 patients experienced disease recurrence. Patients with the hGPX1 wild type had marginally shorter recurrence-free survival compared with those with the hGPX1 variant genotype (log-rank test, P = 0.066). The difference was even greater in whites (log-rank test, P = 0.036). When we performed multivariate analysis using Cox proportional hazards model, we detected a borderline protective role for the hGPX1 variant genotype in recurrence, with a hazard ratio of 0.71 (95% confidence interval 0.48 to 1.05). The protective association was even stronger in whites (hazard ratio 0.63, 95% confidence interval 0.42 to 0.96). CONCLUSIONS: Our findings suggest that a genetic polymorphism in the hGPX1 gene may serve as a molecular marker for monitoring bladder cancer recurrence.

Aged↗