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Biomedical subjects

Xifeng Wu

Publications and source records attributed to Xifeng Wu.

At least 55 records · Page 3Linked to original sources
PubMed2005

Mutagen sensitivity may predict lung protection by amifostine for patients with locally advanced non-small cell lung cancer treated by chemoradiotherapy.

Amifostine (AMF) has been shown to protect some normal tissues from acute effects of radiation therapy +/- chemotherapy. We enrolled 62 patients in a randomized study investigating the efficacy of AMF: 31 had concurrent chemoradiation for non-small cell lung cancer and 31 had the same treatment + AMF. AMF reduced the frequency and severity of esophagitis, pneumonitis, and neutropenic fever. We have tried to identify patients who get more benefit from AMF by checking their DNA repair capability of normal cells. It was hypothesized that DNA repair capacity from patients' lymphocytes damaged by bleomycin could predict their normal tissue sensitivity to chemoradiation and could be protected by AMF. Forty-six of the 62 patients provided pretreatment blood for assessment of mutagen sensitivity (MS) using a peripheral lymphocyte assay that infers DNA repair capacity from cellular damage remaining after in vitro mutagenic exposure and recovery. Bleomycin-induced chromosome breaks in 50 metaphases were counted and expressed as the mean number of breaks per cell. Patients with an average of more than one break/cell were deemed to exhibit the MS phenotype. Data analysis used Pearson's chi-square and Kaplan-Meier survival function estimates with Strata 8.2 statistical software. The Log-rank test was used to assess the equality of survival function using a P value of .05. Twelve patients (10 AMF, 2 control) exhibited the MS phenotype. The remaining 34 patients (13 AMF, 21 control) were considered to have normal DNA repair. There were no significant differences in overall survival, disease specific survival, or local control by MS. Those with high MS had shorter distant metastasis-free survival compared with low MS patients ( P = .029). There were no differences in severe esophagitis or neutropenic fever by MS. Both high and low MS patients from the control group developed severe lung fibrosis compared with five of 21 who had AMF ( P = .025). The incidence of grade 3/4 lung fibrosis was two of 10 with AMF compared with two of two in the control group ( P = .025) with higher MS. Higher MS was associated with shorter distant metastasis-free survival and more frequent grade 3/4 lung fibrosis. AMF reduced the incidence of grade 3/4 lung fibrosis among higher MS. These data suggest that MS might help identify subgroups of patients who could receive more benefit from AMF with respect to lung damage.

Adult↗
PubMed2005

Pharmacogenetics in esophageal cancer.

The current oncology practice of treating cancer with aggressive doses of radiation and chemotherapy is potentially disastrous, as response and side effects vary depending on several factors including pharmacogenetics. This study is the first to evaluate esophageal cancer treatment with a pharmacogenetic paradigm and its application of pharmacogenetic analysis to multiple genes in each drug action pathway as a means of developing a more accurate and consistent risk prediction model. This study has enrolled 235 patients with resectable adenocarcinoma or squamous cell carcinoma of the esophagus who had been treated with chemoradiation followed by esophagectomy. The preliminary finding that methylenetetrahydrofolate reductase polymorphisms modify 5-fluorouracil response supports the hypothesis that response or resistance to therapy in esophageal cancer patients may be modulated by genetic variants involved in the metabolism or mechanism of chemotherapy drug action. Our ongoing esophageal cancer research aims to determine individual pharmacogenetic profiles to identify patients most likely to have chemotherapeutic benefit and patients with the highest risk of suffering genotoxic side effects. These profiles will ideally lead to individualized therapies, improved treatment outcomes, and a movement toward clinically applied pharmacogenetics. This emergent area of biomedicine could lead to substantially improved clinical outcomes for patients with adenocarcinoma or squamous cell carcinoma of the esophagus.

Adenocarcinoma↗
PubMed2005

Polymorphisms in XPD exons 10 and 23 and bladder cancer risk.

INTRODUCTION: The nucleotide excision repair gene, xeroderma pigmentosum complementation group D (XPD), has been hypothesized to have a role in cancer risk, but results from prior molecular epidemiologic studies and genotype-phenotype analyses are conflicting. MATERIALS AND METHODS: We examined the frequency of the XPD Asp312Asn polymorphism in exon 10 and the XPD Lys751Gln polymorphism in exon 23 in 505 incident bladder cancer cases and 486 healthy controls. RESULTS: Overall, the XPD exon 10 and 23 genotypes were not associated with bladder cancer risk, after adjusting for age, sex, ethnicity, and smoking status. A gender-specific role was evident that showed an increased risk for women, but not for men, associated with the variant genotypes for both exons. For example, when the exon 23 variant allele genotypes were combined (Lys/Gln + Gln/Gln), there was an increased bladder cancer risk in women [odds ratio (OR), 1.69; 95% confidence interval (95% CI), 1.12-2.58] but not in men (OR, 0.99; 95% CI, 0.79-1.24; P(interaction) = 0.041; OR, 1.62; 95% CI, 1.02-2.58). There was also a gene-smoking interaction that showed the variant alleles for either exon or the combination of both increase the risk of bladder cancer for light and heavy smokers. For exon 23 (P(interaction) = 0.057; OR, 1.21; 95% CI, 0.99-1.47), heavy smokers (> or = 20 pack-years) who carried the exon 23 variant allele genotypes had an OR of 4.13 (95% CI, 2.53-6.73), whereas heavy smokers with the wild-type genotypes were at lower risk (OR, 3.55; 95% CI, 2.19-5.75). Moderate smokers (1-19 pack-years) with the variant allele genotypes had an OR of 1.54 (95% CI, 0.94-2.53), whereas moderate smokers with the wild-type genotypes had an OR of 1.12 (95% CI, 0.63-1.98). CONCLUSIONS: Although we did not observe main effects associated with the XPD genotypes, these results do suggest the variant allele genotypes were associated with increased bladder cancer risk in women and smokers with statistically significant interactions in the exon 23 polymorphism. Although there is biological plausibility, these novel findings for gender and smoking should be interpreted with caution upon confirmation in larger studies.

Case-Control Studies↗
PubMed2005

A modified host cell reactivation assay to measure DNA repair capacity for removing 4-aminobiphenyl adducts: a pilot study of bladder cancer.

As DNA repair plays an important role in genetic susceptibility to bladder cancer, assessment of the DNA repair phenotype is critical for the molecular epidemiology of bladder cancer. In this study, we developed and applied an assay using the luciferase (luc) reporter gene in a host-cell reactivation assay to measure DNA repair capacity for DNA damage induced by 4-aminobiphenyl (4-ABP), a well-studied aromatic amine and a known bladder carcinogen. We observed a dose-response relationship for 4-ABP dosage and DNA repair capacity (luc activity). We then applied this assay to measure DNA repair capacity in a pilot study of 89 pairs of bladder cancer patients and healthy controls matched by age, gender, and ethnicity, and we found that DNA repair capacity was significantly lower in cases than in controls (13.0% versus 14.4%; P = 0.006). Poor DNA repair capacity was associated with 3.42-fold increased bladder cancer risk. Further analysis revealed that intermediate and low levels of DNA repair capacity increased bladder cancer risk to 3.43-fold and 4.97-fold, respectively, compared with individuals with the most efficient DNA repair capacity. Moreover, ever smokers with suboptimal DNA repair capacity exhibited a 6.06-fold increased risk compared with never smokers with normal DNA repair capacity. In conclusion, our results support the hypothesis that deficient DNA repair capacity for 4-ABP induced DNA damage and increases bladder cancer risk. Our assay provides a new tool to specifically quantify DNA repair capacity in bladder cancer studies and, therefore, contributes to our goal of further elucidating bladder carcinogenesis.

Adult↗
PubMed2005

Case-control analysis of dietary folate and risk of bladder cancer.

Dietary folate, a water-soluble B vitamin found in a variety of fruits and vegetables, is of particular interest as a chemopreventive agent due to its role in DNA methylation and DNA synthesis and repair. We hypothesized that individuals with low folate intake would be at an increased risk for bladder cancer. Using an ongoing case-control study we assessed dietary folate in 409 incident bladder cancer patients and 451 healthy control subjects. A food-frequency questionnaire was used to estimate naturally occurring food folate (microg/kcal/day), dietary folate equivalents (DFE) from food sources (microg DFE/kcal/day), and DFE from all sources (microg DFE/kcal/day). Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Bladder cancer patients reported a statistically significant lower intake of folate than control subjects for food folate and DFE from food sources (P < 0.001) but not for DFE from all sources (P = 0.061). In the highest quartile of food folate intake there was a 54% reduced risk for bladder cancer (OR = 0.46; 95% CI = 0.29-0.73) after adjusting for age, gender, ethnicity, smoking, and total energy intake. Similarly, the highest quartile of intake was associated with a 59% reduced risk for DFE from food sources (OR = 0.41; 95% CI = 0.26-0.65) and a 35% reduced risk for DFE from all sources (OR = 0.65; 95% CI = 0.42-1.00). In the joint-effects analyses using never smokers with high folate intake as the reference group (OR = 1.0), heavy smokers with low food folate intake had a 2.31-fold (95% CI = 1.11-4.82) increased risk, whereas heavy smokers with high folate intake had a reduced OR of 1.31 (95% CI = 0.53-3.26). Although the ORs were not statistically significant, light smokers and high folate intake exhibited a protective effect (OR = 0.62; 95% CI = 0.20-1.94), whereas an increased risk was observed for light smoking and low folate intake (OR = 1.41; 95% CI = 0.57-3.45). These patterns were consistent for the joint effects of smoking and DFE from food sources and DFE from all sources. In summary, high intake of dietary folate was associated with an overall decrease in bladder cancer risk. These data may have important implications for cancer prevention; however, large, hypothesis-driven, population-based clinical trials will be required to confirm these findings.

Case-Control Studies↗
PubMed2005

Mutagen-induced chromatid breakage as a marker of cancer risk.

Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity. This in vitro assay measures the frequency of mutagen-induced breaks in peripheral lymphocytes. Mutagen sensitivity assessed by this method has been shown to be a significant risk factor for tobacco-related malignancies, especially those of the upper aerodigestive tract. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials. This chapter describes methods for and discusses results from studies of mutagen sensitivity as measured by quantifying chromatid breaks induced by chromosome breaking agents, such as the gamma-radiation radiomimetic DNA crosslinking agent bleomycin and chemicals that form so-called bulky DNA adducts, such as 4-NQO and the tobacco smoke constituent, benzo[a]pyrene, in short-term cultured peripheral blood lymphocytes.

Animals↗
PubMed2005

The pharmacogenetic impact of inflammatory genes on bladder cancer recurrence.

Although superficial bladder cancer can generally be treated successfully, tumor recurrence is a serious clinical problem, with a recurrence rate of approximately 70%. Clinicopathologic markers for superficial bladder cancer recurrence remain the best prognostic predictors in clinical decision making. Biomarkers that may complement clinicopathological parameters and increase the accuracy of outcome prediction have been extensively studied. A large number of molecular markers, including inflammatory genes, have been suggested to have predictive value for bladder cancer recurrence. The role of inflammation in the development and progression of bladder cancer, as in other malignancies, is gaining increased recognition. This review will summarize recent data regarding the impact of genetic variations in inflammatory genes on de novo bladder cancer recurrence, as well as recurrence in the context of bacillus Calmette-Guerin (BCG) treatment. Genomic variation as a mechanism that may modify BCG efficacy is discussed in detail.

BCG Vaccine↗
PubMed2004

Effects of N-acetyl transferase 1 and 2 polymorphisms on bladder cancer risk in Caucasians.

Cigarette smoking is the predominant risk factor for bladder cancer (BC). Major carcinogens present in tobacco smoke include a number of aromatic and heterocyclic amines. Two distinct N-acetyl transferase (NAT) enzymes, NAT1 and NAT2, play important roles in the bio-activation and detoxification of these carcinogens. Genes encoding NAT1 and NAT2 are highly polymorphic among human populations, and these polymorphisms result in rapid or slow acetylator phenotypes. Recent studies have suggested that variant alleles leading to slow acetylation by the NAT2 enzyme or rapid acetylation by the NAT1 enzyme constitute possible risk factors for bladder cancer. In this case-control study, we sought to determine whether NAT1 and NAT2 polymorphisms are associated with bladder cancer risk in the largest sample size to date. PCR-RFLP assay was used to determine the presence of NAT1 and NAT2 polymorphisms in 507 Caucasian BC patients and 513 age-, gender-, and ethnicity-matched healthy controls. Overall, we found no significant association between BC risk and NAT1 NAT1*10 allele (OR=0.95; 95% CI 0.73-1.25). However, our data suggested that NAT2 slow acetylator genotypes were associated with a significant increased risk of BC (OR=1.31; 95% CI, 1.01-1.70). This elevated risk appeared more evident in older individuals (OR=1.41; 95% CI, 1.01-1.98) than in younger individuals (OR=1.15; 95% CI, 0.76-1.74). Moreover, the risk was greater for heavy smokers (OR=2.11; 95% CI, 1.33-3.35) than light smokers (OR=0.96; 95% CI, 0.61-1.53) and never smokers (OR=1.23; 95% CI, 0.79-1.90). Finally, a joint effect between NAT2 slow acetylators and heavy smokers was observed. Using never smokers with NAT2 rapid acetylator genotypes as a reference group, heavy smokers with NAT2 slow acetylator genotypes showed an over six-fold increase in BC risk. In a multiplicative interaction model, the interaction term was statistically significant (P=0.02). Our data suggest that having a NAT2 slow acetylator genotype is a significant risk factor for BC, particularly in smokers and older individuals.

Acetylation↗
PubMed2004

A functional polymorphism in RGS6 modulates the risk of bladder cancer.

RGS proteins negatively regulate heterotrimeric G protein signaling. Recent reports have shown that RGS proteins modulate neuronal, cardiovascular, and lymphocytic activity, yet their role in carcinogenesis has not been explored. In an epidemiologic study of 477 bladder cancer patients and 446 matched controls, three noncoding single-nucleotide polymorphisms (SNPs) in RGS2 and RGS6 were each associated with a statistically significant reduction in bladder cancer risk. The risk of bladder cancer was reduced by 74% in those individuals with the variant genotype at all three SNPs (odds ratio, 0.26; 95% confidence interval, 0.09-0.71). When the SNPs were analyzed separately, the RGS6-rs2074647 (C-->T) polymorphism conferred the greatest overall reduction in risk of bladder cancer (odds ratio, 0.66; 95% confidence interval, 0.46-0.95). These reductions in risk were more pronounced in ever smokers, suggesting a gene-environment interaction. In transfection assays, the RGS6-rs2074647 (C-->T) polymorphism increased the activity of a luciferase-RGS fusion protein by 2.9-fold, suggesting that this SNP is functionally significant. Finally, we demonstrate that RGS2 transcripts and several splice variants of RGS6 are expressed in bladder cancer cells. These data provide the first evidence that RGS proteins may be important modulators of cancer risk and validate RGS6 as a target for further study.

Case-Control Studies↗
PubMed2004

Genetic susceptibility to tobacco-related cancer.

Although cigarette smoking is the dominant risk factor for several epithelial cancers, only a small fraction of individuals with tobacco exposure develop cancer. The underlying hypothesis is that genetic factors may render certain smokers more susceptible to cancer than others. Genetic alterations in critical regulatory pathways may predispose cells to carcinogenesis. These pathways include regulation of xenobiotic metabolism; control of genomic stability, including DNA repair mechanisms, cell-cycle checkpoints, apoptosis and telomere length; and control of microenvironmental factors, such as matrix metalloproteinases, inflammation and growth factors. In addition, epigenetic events, such as promoter hypermethylation and loss of imprinting, are also involved in carcinogenesis. In this review, we will summarize recent advances in genetic susceptibility to tobacco-related cancer. Emphasizing on risk assessment, we will describe how genetic variations in the above-mentioned genetic pathways modify the tobacco-related cancer risk. In addition, we will discuss how genetic variations may assist in predicting clinical outcome, such as the natural history of cancer and treatment response. The measurements of genetic susceptibility by both genotypic and phenotypic assays are covered in the text. Finally, we present a number of current concerns that need to be addressed as the exciting field of molecular cancer epidemiology advances rapidly.

Cytochrome P-450 Enzyme System↗
PubMed2004

Serum levels of insulin growth factor (IGF-I) and IGF-binding protein predict risk of second primary tumors in patients with head and neck cancer.

PURPOSE: Second primary tumors (SPTs) are a hallmark of head and neck squamous cell carcinomas (HNSCCs). Serum levels of insulin growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with subsequent development of several epithelial cancers in prospective studies. EXPERIMENTAL DESIGN: To examine the role of IGFs in SPT development, we conducted a nested case-control study within a randomized, placebo-controlled chemoprevention trial in patients with early-stage HNSCC. We compared prediagnostic serum IGF-I and IGFBP-3 levels in 80 patients who subsequently developed SPTs and 173 controls (patients without SPTs) matched to the cases on age (+/-5 years), sex, ethnicity, year of randomization, and length of follow-up. RESULTS: The cases exhibited significantly higher levels of IGF-I and IGFBP-3 than did the controls (P = 0.001 and 0.019, respectively). Elevated IGF-I levels were associated with a 3.66-fold significantly increased risk of SPT. Lower and higher IGFBP-3 levels were associated with a 2.22- and 7.12-fold significant increased risk, respectively. The median SPT-free time was significantly shorter in patients with higher IGF-I levels than in patients with lower IGF-I levels (P < 0.0001). A similar trend was observed for IGFBP-3 (P = 0.002). Moreover, in the Cox proportional hazards model, higher IGF-I levels were significantly associated with increased risk of SPT with a hazard ratio of 2.78. Patients with the lower and higher IGFBP-3 levels also exhibited significantly increased risks with hazard ratios of 1.65 and 2.17, respectively. CONCLUSIONS: This is the first study demonstrating that higher IGF-I levels, and lower and higher IGFBP-3 levels are risk factors for SPT development. Thus, measuring serum IGF-I and IGFBP-3 levels may be useful markers in assessing the risk of second tumors in patients successfully treated for their index cancer.

Adult↗
PubMed2004

Methyl-CpG-binding domain 2: a protective role in bladder carcinoma.

BACKGROUND: MBD2, a methyl-CpG-binding domain 2 protein, has attracted much attention because of its role in epigenetic regulation of gene expression. In addition to transcriptional repression, MBD2 has also been shown to catalyze demethylation by directly removing methyl groups from 5-methylcytosine residues in DNA. Although the demethylase activity of MBD2 remains controversial, reduction of MBD2 messenger RNA expression has been observed in various tumor tissue types. In the current case-control study, the authors investigated the association between MBD2 expression and bladder carcinoma risk. METHODS: RNA was isolated from the peripheral blood lymphocytes of 98 bladder carcinoma case patients and 135 frequency-matched control patients. MBD2 expression was measured by real-time quantitative reverse transcription-polymerase chain reaction assays. RESULTS: Overall, there was a significantly reduced risk associated with high levels of MBD2 expression (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.21-0.90). This relation was maintained when the data were categorized according to quartile distribution for MBD2 expression (P for trend < 0.05). It is noteworthy that the protective effects were more apparent in women (OR, 0.25; 95% CI, 0.06-1.02) compared with men (OR, 0.58; 95%; CI, 0.24-1.42), in older individuals (OR, 0.12; 95% CI, 0.03-0.45) compared with younger individuals (OR, 1.16; 95% CI, 0.40-3.33), and in heavier smokers (OR, 0.40; 95% CI, 0.18-0.93) compared with lighter smokers (OR, 0.71; 95% CI, 0.18-2.86). CONCLUSIONS: Although the underlying molecular mechanisms remain unclear, the data obtained in the current study represent the first evidence demonstrating a protective role against bladder carcinoma risk for MBD2. MBD2 expression may prevent age-related, gender-related, and smoking-induced hypermethylation, which are predisposing factors for tumor development.

Base Sequence↗
PubMed2004

Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study.

Epidemiological studies have shown an association between low folate intake and an increased cancer risk. Major genes involved in folate metabolism include methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS). We investigated joint effects of polymorphisms of the MTHFR (677 C-->T, 1298A-->C) and MS genes (2756 A-->G), dietary folate intake and cigarette smoking on the risk of bladder cancer in a case-control study. The study population consisted of 457 bladder cancer patients and 457 healthy controls, matched to the cases in terms of age, gender and ethnicity. Genotype data were analyzed in a subset of 410 Caucasian cases and 410 controls. Compared with individuals carrying the MTHFR 677 wild-type (CC) and reporting a high folate intake, those carrying the variant genotype (CT or TT) and reporting a low folate intake were at a significantly 3.51-fold increased risk of bladder cancer (95% CI: 1.59-6.52). In contrast, individuals carrying a variant genotype and reporting a high folate intake were at only a 1.39-fold increased risk (95% CI: 0.71-2.70), and those carrying the wild-type and reporting a low folate intake were at only 1.56-fold increased risk (95% CI: 0.82-2.97). The interaction between genetic polymorphisms and folate intake was significant on the multiplicative scale (P = 0.01). When analyzed in the context of smoking status, compared with never smokers with the MTHFR 677 wild-type, the risk increased to 6.56-fold (95% CI: 3.28-13.12) in current smokers carrying the variant genotype. Analyses of the MTHFR 1298, MS 2756 genes revealed similar results. In addition, age at cancer onset in former smokers increased as the proportion of the heteromorphic haplotype in the individual increased (P = 0.005). Our results strongly suggest that polymorphisms of the MTHFR and MS genes act together with low folate intake and smoking to increase bladder cancer risk. These results have important implications for cancer prevention in susceptible populations.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2004

An evolutionary perspective on single-nucleotide polymorphism screening in molecular cancer epidemiology.

Given that there are millions of single-nucleotide polymorphisms (SNPs) in the entire human genome, a major difficulty faced by scientists in planning costly population-based genotyping is to choose target SNPs that are most likely to affect phenotypic functions and ultimately contribute to disease development. Although it is widely accepted that sequences with important functionality tend to be less variable across species because of selective pressure, to what extent evolutionary conservation is mirrored by epidemiological outcome has never been demonstrated. In this study, we surveyed odds ratios detected for 46 SNPs in 39 different cancer-related genes from 166 molecular epidemiological studies. The conservation levels of amino acid that these SNPs affected were calculated as a tolerance index by comparing sequences from different species. Our results provide evidence of a significant relationship between the detected odds ratios associated with cancer risk and the conservation levels of the SNP-affected amino acids (P = 0.002; R(2) = 0.06). Tolerance indices were further calculated for 355 nonsynonymous SNPs identified in 90 human DNA repair genes, of which 103 caused amino acid changes in very conserved positions. Our findings support the concept that SNPs altering the conserved amino acids are more likely to be associated with cancer susceptibility. Using such a molecular evolutionary approach may hold great promise for prioritizing SNPs to be genotyped in future molecular epidemiological studies.

Alleles↗
PubMed2004

Hormone replacement therapy and lung cancer risk: a case-control analysis.

PURPOSE: To date, there are few published data regarding the use of hormone replacement therapy (HRT) and lung cancer risk. Therefore, we analyzed data regarding HRT use from a large case-control study designed to study genetic susceptibility to lung cancer to determine whether HRT affected risk of lung cancer. EXPERIMENTAL DESIGN: In a secondary analysis, we compared self-reported HRT use among 499 women with lung cancer and 519 healthy age-matched controls. RESULTS: HRT use was associated with an overall reduced risk of 34% [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.51-0.89] of lung cancer, after adjusting for age, ethnicity, smoking status, education, body mass index, and menopausal status. The use of estrogen replacement therapy alone was associated with a 35% reduction in lung cancer risk (OR, 0.65; 95% CI, 0.47-0.89) and the use of combination therapy (estrogen and progestin) was associated with a 39% reduction in lung cancer risk (OR, 0.61; 95% CI, 0.40-0.92). HRT use was also associated with a statistically significantly reduced risk of lung cancer in current smokers (OR, 0.59; 95% CI, 0.38-0.92), but the risk estimates were not statistically significant in never (OR, 0.72; 95% CI, 0.37-1.40) or former smokers (OR, 0.73; 95% CI, 0.46-1.15). In addition, as the cigarette pack-years increased among ever smokers, the protective effect diminished, so that light smokers appeared to benefit the most from HRT use. Decreased lung cancer risks were also evident when the data were stratified by age, ethnicity, and body mass index. The joint effects of HRT use and mutagen sensitivity suggest that HRT use modifies lung cancer risk for genetically susceptible women. HRT use was also associated with a lower risk of death and improved survival compared with the women not taking HRT. To provide a possible biological mechanism to explain our findings, we compared plasma levels of insulin-like growth factor I in users and nonusers, and demonstrated that HRT use was associated with statistically significantly lower insulin-like growth factor I levels for both cases and controls compared with non-HRT users. CONCLUSIONS: These data suggest an association of HRT use with a decrease in lung cancer risk. However, there are several limitations to this secondary analysis, requiring that the data be viewed with caution, and confirmation is required in well-designed hypothesis driven studies. The biological role of HRT in lung cancer remains understudied, and only extensive research can yield new insights into the mechanisms underlying a protective effect of HRT for lung cancer.

Age Distribution↗
PubMed2004

Benzo[a]pyrene diol epoxide-induced 9p21 aberrations associated with genetic predisposition to bladder cancer.

CDKN2A, 9p21, encodes two alternatively spiked, functionally distinct, tumor-suppressor proteins, P16INK4A and P14ARF, which play active roles in the RB1 and TP53 pathways, respectively. Deletion of 9p is one of the most frequent genomic alterations in bladder cancer. In addition, alterations of 9p21 and P16 are frequently seen in the epithelial cells of chronic smokers. This pilot study evaluated whether 9p21 aberrations induced by exposure in vitro to benzo[a]pyrene diol epoxide (BPDE), the metabolic product of benzo[a]pyrene, a constituent of tobacco smoke, were more common in the peripheral blood lymphocytes of 61 bladder cancer patients compared to 64 matched controls. Our hypothesis was that 9p21 sensitivity to BPDE reflects the susceptibility of a specific locus to damage from carcinogens in tobacco smoke. We found that BPDE-induced chromosome band 9p21 aberrations were significantly higher in lymphocytes of bladder cancer cases (24.97 +/- 5.26 per 1,000) than in controls (20.72 +/- 4.51 per 1,000; P < 0.0001). However, no difference was observed for CEP9, a control locus. After adjustment for age, sex, ethnicity, and smoking status, 9p BPDE sensitivity had an odds ratio (OR) of 9.01 [95% confidence interval (95% CI) 3.75, 21.67] for bladder cancer. We further observed a gradient of elevated bladder cancer risk associated with increasing chromosomal damage. The adjusted ORs for subjects in the second, third, and highest quartiles of BPDE-induced 9p21 aberrations relative to the first quartile were 0.48 (0.04, 5.69), 5.14 (1.12, 23.59), and 21.51 (4.75, 97.34), respectively, providing increasing dose-response evidence of the locus-specific alterations. Thus, 9p21 may be a molecular target for BPDE-induced damage in bladder cancer cases.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2004

Specific chromosome aberrations in peripheral blood lymphocytes are associated with risk of bladder cancer.

Specific chromosome aberrations in peripheral blood lymphocytes (PBLs) in chromosomes 9 and 11 may be associated with bladder cancer. To investigate this hypothesis, in this study, we used a whole-chromosome painting technique to detect chromosomal aberrations in PBLs from 100 patients with bladder cancer and 100 matched controls. We also used a locus-specific fluorescence in situ hybridization technique to study 9p21 and cyclin D1 gene (CCND1) aberrations in PBLs of 10 patients and 10 controls and in tumor tissues of 38 additional cases. The chromosome-painting analysis showed that there were more aberrations of chromosomes 9 and 11 in bladder cancer patients than in controls. When categorized by type, the number of deletions of 9p and of translocations of chromosome 11 was significantly higher in patients than in controls (P < 0.05). Stratified analysis showed a larger odds ratio (OR) for bladder cancer in individuals with either a 9p deletion or a chromosome 11 translocation/amplification and an even larger OR in individuals with both aberrations. Using locus-specific analysis, we found that 9p21 aberrations occurred more frequently in bladder cancer patients (12.1 per 1,000 interphase cells) than in controls (6.4 per 1,000 interphase cells, P < 0.05); CCND1 translocation and amplification were observed only in bladder cancer patients. Tumor tissue analysis showed that aberrations of 9p21 (40.0 per 100 interphase cells) and CCND1 (43.8 per 100 interphase cells) were very common. Thus, we concluded that 9p deletions and translocations of chromosome 11, especially at 9p21 and CCND1, are associated with bladder cancer.

Chromosome Aberrations↗