Smoking Bladder Cancer Research Articles

Urinary Cotinine: A Promising Marker of Recurrence of Non-muscle Invasive Bladder Tumor

Introduction and objectives: Nicotine is well known to be an addictive compound of tobacco, but it is not primarily carcinogenic. It is metabolized to cotinine, which is considered the best marker of tobacco exposure. Little is known whether recurrence rate of bladder cancer is related to nicotine metabolites eliminated in urine. We aim by this study to evaluate the relation between urinary cotinine level and the recurrence of bladder cancer. Materials and Methods: Between January 2018 and June 2022, a cross sectional study was conducted. Enrolled patients were smokers already diagnosed with non-muscle invasive bladder cancer, treated by resection only, and presenting for a follow up cystoscopy. Included patients had unchanged smoking habits in the day before the procedure, same ethnicity (Caucasians) and no additional professional exposure. Cotinine level was measured on a sample of voided urine before cystoscopy. Tumor recurrence was considered positive independently from the histological type, and was assessed by direct vision cystoscopy. Patients were considered moderate or heavy smokers depending on the level of cotinine in their urine samples (< or > 550 ng/ml respectively). A Fisher Exact Test was used to assess the relationship between variables. Results: A total of 135 patients was included. Mean age was 64 years (range 36 to 78). The mean duration of smoking was 30.3 years. Urinary cotinine level was > 550 ng/ml in 80 patients (59.26%) and < 550 ng/ml in 55 patients (40.74%). Recurrence was identified in 70 patients (51.85%) and was absent in the remaining 65 (48.15%). Recurrence was observed in 68.75% of the heavy smokers and in 27.27 % of moderate smokers. Cotinine level higher than 550 ng/mL was linked to an increased risk of bladder cancer, with a relative risk of 4.16 (p-value < 0,025). Conclusion: High urinary cotinine levels (>550 ng/ml) conveys a 4 folds’ risk for the recurrence of bladder cancer in smokers. Additional prospective studies are needed to better understand the relation between urinary cotinine levels and bladder cancer, and its usefulness in bladder cancer surveillance.

Trajectory of smoking and early bladder cancer risk among Korean young adult men

ObjectivesThe aim of this study was to examine the risk of bladder cancer according to the trajectory pattern of amount of smoking among Korean young adult men.MethodsSmoking status was assessed with a standardized questionnaire in the Korean Life Course Health Study (KLCHS). Trajectory analyses were performed among young adult men using seven repeated surveys of cigarette per day (CPD) every two years from 1992 to 2005. The occurrence of bladder cancer was tracked from 2006 to 2016. The Cox proportional models were used to calculate the hazard ratio (HR) (95% confidence interval) of smoking patterns on bladder cancer.ResultsThe mean (standard deviation) age of the 161,069 participants was 34.0 (3.9) years, and 2,280,143 person-years (PY) were examined during the follow-up period of 14.2 (median 14.3) years. During this period, 263 new cases of bladder cancer occurred (11.5/100,000 PY). Among the six trajectory groups (low steady, lowering, rise and fall, high steady, rise and sharp fall, and very high steady), there was a higher risk of developing bladder cancer in the all the other groups compared to the low steady group. The highest risk group was the very high steady group, with HR 2.83 (95% CI 1.79–4.49). In addition, the risk of bladder cancer was 2.61 (95% CI 1.50–4.54) in the rise and sharp fall group.ConclusionThe risk of bladder cancer did not show much difference according to trajectories, except for low steady group. Thus quitting smoking should be the priority to lower the risk of bladder cancer in smokers.

Molecular Characterization of Bladder Cancer in Smokers versus Nonsmokers

Smoking is considered an important risk factor for bladder cancer (BC), yet molecular characterization of BC in nonsmokers has not been extensively studied. Here, we compare molecular differences between smokers and nonsmokers with BC. BC specimens (676) profiled at a Clinical Laboratory Improvement Amendments-certified laboratory from 2006 to 2014 were retrospectively evaluated for molecular differences between smokers and nonsmokers. Protein expression was determined with immunohistochemistry. In situ hybridization was used for ERBB2 (HER2/neu) and EGFR evaluation. Genes were evaluated using Sanger or next-generation sequencing. Thirty patients were confirmed lifetime nonsmokers (NS) and 39 were reformed or current smokers (RCS). There was a trend for increased PIK3CA mutations in NS versus RCS (43% vs 11%, p=0.1760), whereas TP53 alterations were higher in RCS versus NS (63% vs 53%, p=0.6699). EGFR amplification was observed more in NS versus RCS (22% vs 11%, p=0.5815), while HER2 was amplified only in RCS (23% vs 0%, p=0.05). The molecular differences between RCS and NS with BC suggest a different oncogenesis with potentially different treatment options. Patient summaryBladder cancer patients with no history of smoking have different molecular characteristics than those with smoking history. We found that smokers tend to have higher incidence of HER2 amplification, whereas nonsmokers seemed to have higher PIK3CA mutation. This knowledge provides essential information, which can bear relevance to treatment options.

Molecular characterization of bladder cancer in smokers versus non-smokers.

4528 Background: Bladder cancer (BC) is one of the most common malignancies of the urinary tract and is 4thmost common cancer among men. It is estimated that by the end of 2015, the US will have ap...

Does quantification of smoking history correlate with initial bladder tumor grade and stage?

The causal association between cigarette smoking and urothelial bladder cancer has been firmly established for several decades. However, the impact of smoking intensity on initial tumor aggressiveness is less established and is reviewed in this manuscript. Particular attention is given to the relation between smoking history with both muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). This article also briefly reviews the epidemiologic evidence, smoking-associated carcinogenesis, and the limitations of quantifying smoking history. There is evidence to suggest that smokers have a three-fold increased risk of developing invasive bladder cancer compared to non-smokers, and smoking cessation can reduce this risk. Continued efforts should be made to raise awareness of bladder cancer in smokers and to advocate further for smoking cessation.

GSTP1 Gene Ile105Val Polymorphism Causes an Elevated Risk for Bladder Carcinogenesis in Smokers

The glutathione S transferase (GST) family of enzymes plays a vital role in the phase II biotransformation of environmental carcinogens, pollutants, drugs and other xenobiotics. GSTs are polymorphic and polymorphisms in GST genes have been associated with cancer susceptibility and prognosis. GSTP1 is associated with risk of various cancers including bladder cancer. A case control study was conducted to determine the genotype distribution of GSTP1 A>G SNP, to elucidate the possible role of this SNP as a risk factor in urinary bladder cancer (UBC) development and to examine its correlation with clinico-pathologic variables inUBC cases. Using the polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP) approach, we tested the genotype distribution of 180 bladder cancer patients in comparison with 210 cancer-free controls from the same geographical region with matched frequency in age and gender. We did not observe significant genotype differences between the control and bladder cancer patients overall with an odds ratio (OR)=1.23 (p>0.05). The rare allele (AG+GG) was found to be present more in cases (28.3%) than in controls (24%), though the association was not significant (p<0.05). However, a significant risk of more than 2-fold was found for the variant allele (AG+GG) with smokers in cases as compared to controls (p>0.05). Thus, it is evident from our study that GSTP1 SNP is not implicated overall in bladder cancer, but that the rare, valine-related allele is connected with higher susceptibility to bladder cancer in smokers and also males.

Abstract 3622: Further observation of increasing strength of the smoking-bladder cancer association: The Los Angeles Bladder Cancer Study.

Abstract Objective: Cigarette smoking is an established risk factor for bladder cancer. Recent research suggests smoking-related risk has increased in the United States, in spite of decreased prevalence of smoking (JNCI 101:1553-61, 2009; JAMA 306:737-45, 2011). Hypothesized reasons for this temporal pattern include changes in how deeply smokers inhale and changes in cigarette composition, which may be related. We examined associations between smoking status and bladder cancer risk during three successive intervals between 1987 and 1996 to investigate whether level of risk had changed in our study population. To gain insight into possible effects of changing smoking habits we also evaluated impact on estimated associations of intensity and duration of smoking. Methods: We examined the association between smoking and bladder cancer risk in a population-based case-control study conducted in Los Angeles within three separate intervals defined by year of diagnosis: 1987-1989, 1990- 1992, and 1993-1996. We calculated odds ratios (OR) and corresponding 95% confidence intervals (CI) using conditional logistic regression. Cases and controls were matched on age, gender, race, and neighborhood. Further analyses were adjusted for pack years of smoking, education, and use of non-steroidal anti-inflammatory drugs (NSAIDs). Results: There were 569 cases and 553 controls in the 1987-1989 interval, 461 cases and 426 controls in 1990-1992, and 641 cases and 607 controls in 1992-1996. In each interval smoking was associated with bladder cancer risk. Compared with never smokers, OR estimates for former smokers were 1.79 [95%CI=1.30-2.48], 1.38 [95%CI=0.95-1.99], and 1.93 [95%CI=1.42-2.62] for the successive intervals. For current smokers, corresponding estimates were 3.18 [95%CI=2.29-4.4], 3.90 [95%CI=2.64-5.77], and 4.75 [95%CI=3.37-6.7]. When males and females were considered separately, these estimates were also greater in later intervals. In 1992-1996, current male smokers were 4.45 (95%CI=3.03-6.56) times as likely and current female smokers were 5.95 (95%CI=2.78-12.71) times as likely to have bladder cancer; these associations were weaker in 1987-1989: 2.95 (95%CI=2.01-4.35) and 3.75 (95%CI=2.03-6.92). After adjusting for pack years, all odds ratio estimates for current smokers were attenuated, 0.83 [95%CI=1.22-2.75], 1.86[95%CI=1.13-3.06], 2.4 [95%CI=1.54-3.75] for successive intervals, while for former smokers none of the associations were statistically significant. Conclusions: Bladder cancer risk appears to have increased among both ever smokers and current smokers, although distinctions are less pronounced after accounting for pack years of smoking. Further research is needed to learn whether this pattern reflects changes in smoking behavior, formulation of cigarettes, or other factors - and to determine whether these increases have continued. Citation Format: Donna C. Dueker, Mariana C. Stern, David V. Conti, Malcolm C. Pike, Victoria K. Cortessis. Further observation of increasing strength of the smoking-bladder cancer association: The Los Angeles Bladder Cancer Study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3622. doi:10.1158/1538-7445.AM2013-3622

Distinct SNP Combinations Confer Susceptibility to Urinary Bladder Cancer in Smokers and Non-Smokers

Recently, genome-wide association studies have identified and validated genetic variations associated with urinary bladder cancer (UBC). However, it is still unknown whether the high-risk alleles of several SNPs interact with one another, leading to an even higher disease risk. Additionally, there is no information available on how the UBC risk due to these SNPs compare to the risk of cigarette smoking and to occupational exposure to urinary bladder carcinogens, and whether the same or different SNP combinations are relevant in smokers and non-smokers. To address these questions, we analyzed the genotypes of six SNPs, previously found to be associated with UBC, together with the GSTM1 deletion, in 1,595 UBC cases and 1,760 controls, stratified for smoking habits. We identified the strongest interactions of different orders and tested the stability of their effect by bootstrapping. We found that different SNP combinations were relevant in smokers and non-smokers. In smokers, polymorphisms involved in detoxification of cigarette smoke carcinogens were most relevant (GSTM1, rs11892031), in contrast to those in non-smokers with MYC and APOBEC3A near polymorphisms (rs9642880, rs1014971) being the most influential. Stable combinations of up to three high-risk alleles resulted in higher odds ratios (OR) than the individual SNPs, although the interaction effect was less than additive. The highest stable combination effects resulted in an OR of about 2.0, which is still lower than the ORs of cigarette smoking (here, current smokers' OR: 3.28) and comparable to occupational carcinogen exposure risks which, depending on the workplace, show mostly ORs up to 2.0.

Smoking–Bladder Cancer Link Strengthened

Smoking–Bladder Cancer Link Strengthened

Are Glutathione S -Transferase Null Genotypes “Null and Void” of Risk for Ischemic Vascular Disease?

The major risk factors for cardiovascular disease (CVD) relate to intrinsic changes in cholesterol metabolism or blood pressure regulation or to diseases such as diabetes. In addition, it has been found that chemical and pollutant exposure has adverse effects on cardiovascular health. Although we have known about the harmful effects of smoking on heart disease for a long time, recent research shows that exposure to other environmental pollutants such as ambient air particles, automobile exhaust, and pesticides can also increases CVD risk.1 It is therefore reasonable to expect that CVD risk could be modified by metabolic processes that detoxify foreign chemicals (xenobiotics) or even endogenous toxins (eg, products of lipid peroxidation). The concept that the mechanisms of detoxification regulate disease susceptibility is one of the cornerstones of cancer research; however, only recently have we begun to appreciate the cardiovascular implications of this concept. Article see p 418 For the most part, the relationships between CVD and detoxification mechanisms remain unknown. Glutathione S -transferases (GSTs), however, are one exception. These enzymes catalyze the conjugation of glutathione with electrophilic xenobiotics.2 In Phase II detoxification reactions, they transform xenobiotics into usually less reactive, water-soluble compounds that are excreted in urine or bile. Genetic variations and deletion genotypes of GSTs are relatively prevalent in human populations. Several studies have suggested that variations in GSTs alter CVD risk particularly in smokers, but the data are inconsistent. Some studies report strong interactions between GST genotypes and smoking, whereas others have found no significant association. The current study by Norskov et al,3 published in this issue of Circulation: Cardiovascular Genetics , is the most highly powered epidemiological study to date that investigates the contribution of GSTs to CVD risk specifically for ischemic heart disease (IHD) and cerebrovascular disease. Norskov et al studied the gene …

Bladder Cancer Predisposition: A Multigenic Approach to DNA-Repair and Cell-Cycle–Control Genes

The candidate-gene approach in association studies of polygenic diseases has often yielded conflicting results. In this hospital-based case-control study with 696 white patients newly diagnosed with bladder cancer and 629 unaffected white controls, we applied a multigenic approach to examine the associations with bladder cancer risk of a comprehensive panel of 44 selected polymorphisms in two pathways, DNA repair and cell-cycle control, and to evaluate higher-order gene-gene interactions, using classification and regression tree (CART) analysis. Individually, only XPD Asp312Asn, RAG1 Lys820Arg, and a p53 intronic SNP exhibited statistically significant main effects. However, we found a significant gene-dosage effect for increasing numbers of potential high-risk alleles in DNA-repair and cell-cycle pathways separately and combined. For the nucleotide-excision repair pathway, compared with the referent group (fewer than four adverse alleles), individuals with four (odds ratio [OR] = 1.52, 95% CI 1.05-2.20), five to six (OR = 1.81, 95% CI 1.31-2.50), and seven or more adverse alleles (OR = 2.50, 95% CI 1.69-3.70) had increasingly elevated risks of bladder cancer (P for trend <.001). Each additional adverse allele was associated with a 1.21-fold increase in risk (95% CI 1.12-1.29). For the combined analysis of DNA-repair and cell-cycle SNPs, compared with the referent group (<13 adverse alleles), the ORs for individuals with 13-15, 16-17, and >or=18 adverse alleles were 1.22 (95% CI 0.84-1.76), 1.57 (95% CI 1.05-2.35), and 1.77 (95% CI 1.19-2.63), respectively (P for trend = .002). Each additional high-risk allele was associated with a 1.07-fold significant increase in risk. In addition, we found that smoking had a significant multiplicative interaction with SNPs in the combined DNA-repair and cell-cycle-control pathways (P<.01). All genetic effects were evident only in "ever smokers" (persons who had smoked >or=100 cigarettes) and not in "never smokers." A cross-validation statistical method developed in this study confirmed the above observations. CART analysis revealed potential higher-order gene-gene and gene-smoking interactions and categorized a few higher-risk subgroups for bladder cancer. Moreover, subgroups identified with higher cancer risk also exhibited higher levels of induced genetic damage than did subgroups with lower risk. There was a significant trend of higher numbers of bleomycin- and benzo[a]pyrene diol-epoxide (BPDE)-induced chromatid breaks (by mutagen-sensitivity assay) and DNA damage (by comet assay) for individuals in higher-risk subgroups among cases of bladder cancer in smokers. The P for the trend was .0348 for bleomycin-induced chromosome breaks, .0036 for BPDE-induced chromosome breaks, and .0397 for BPDE-induced DNA damage, indicating that these higher-order gene-gene and gene-smoking interactions included SNPs that modulated repair and resulted in diminished DNA-repair capacity. Thus, genotype/phenotype analyses support findings from CART analyses. This is the first comprehensive study to use a multigenic analysis for bladder cancer, and the data suggest that individuals with a higher number of genetic variations in DNA-repair and cell-cycle-control genes are at an increased risk for bladder cancer, confirming the importance of taking a multigenic pathway-based approach to risk assessment.

Is bladder cancer more common among opium addicts?

Many environmental and occupational risk factors have been proposed for bladder cancer, among which opium consumption has been considered in few studies. We designed a study to determine the relationship between opium consumption and bladder cancer. In a retrospective, case-control study, male patients with bladder cancer, who had been referred to our hospital in a three-year period, were selected. Data regarding age, gender, smoking, and opium consumption were collected from patients' records and compared with data of a control group, consisting of patients with benign prostatic hyperplasia (BPH). Fifty-two male patients with bladder tumor (group 1) were compared with 108 patients with BPH (group 2). Of the patients with bladder cancer, 36 (68%) were smokers, of whom 12 were also opium addicts. In general, 13 (25.5%) patients were opium consumers (one opium consumer was not smoker). From 108 patients with BPH, 25 (23%) were smokers, of whom, 5 were also opium addicts. Mean duration of cigarette smoking was 31 +/- 13.6 and 20.2 +/- 14.7 years in patients with bladder cancer and BPH, respectively. The duration of opium consumption was 11.9 +/- 1.4 and 6.2 +/- 1.3 years in groups 1 and 2, respectively. The duration of cigarette smoking and opium consumption in group 1 was greater than that in group 2. In addition, smoking increases the risk of bladder cancer 3.8-fold (OR = 8.3, 95% CI = 1.8-7.8). Simultaneous cigarette smoking and opium consumption increases the risk of bladder cancer 6.2-fold (OR = 6.2, 95% CI = 2.04-18.7). There are few studies regarding the carcinogenic effect of opium on bladder. We demonstrated that, the incidence of bladder cancer in smokers, who are simultaneously opium consumers, was higher than in patients who were only smokers. Simultaneous opium addiction and cigarette smoking may have some roles in the pathogenesis of bladder tumor. However, further studies with large sample sizes are warranted.

Glutathione S-transferase π-isoform is not altered in bladder tissue from smokers

Glutathione S-transferase π (GSTπ)-isoform is a cytosolic enzyme involved in the detoxification of reactive metabolites generated from environmental pollutants and cigarette smoke. Although cigarette smoking has been implicated in the etiology of bladder cancer, no information yet exists regarding GSTπ in smokers and nonsmokers. This study was carried out to evaluate the immunohistochemical localization and to measure levels of immunoreactive GSTπ in bladder tissue from smokers and nonsmokers. Tissues from patients diagnosed with transitional cell carcinoma (TCC) were obtained from paraffin embedded blocks fixed in formalin. Bladder tissues from smokers (n = 7) and nonsmokers (n = 8), and histologically confirmed cancerous and noncancerous areas of the same patients (n = 10) were studied. The immunoreactive GSTπ was quantified by calculating its optical density with a computerized Olympus BH-2 microscope connected to a DAGE camera. Immunohistochemical staining for GSTπ appeared to be evenly distributed in the cytosol of the transitional epithelium (TE) of the noncancerous regions. In the TE from patients with advanced TCC, the staining intensity appeared to be stronger in the nuclei relative to cytoplasm, an effect that was even more pronounced in poorly differentiated cancers and in cancers with squamoid features. The immunoreactive levels of GSTπ in the superficial TE cells was approximately 1.7-fold higher compared with the rest of the TE layer (p < 0.05) in smokers and nonsmokers. No significant differences (p > 0.05) were observed between smokers and nonsmokers in either of these regions. The higher concentration of GSTπ in the TE is suggestive of the protective role of this enzyme, serving to prevent any potentially harmful xenobiotics from entering the bladder tissue. The lack of differences in the detoxifying enzymes between smokers and nonsmokers suggests that the increased susceptibility of bladder cancer in smokers is probably mediated by other mechanisms.

Aromatic amines and cancer.

Epidemiological evidence on the relation between aromatic amines and cancer risk is reviewed. In particular, cancer risk in humans resulting from exposure to aromatic amines from occupational sources and tobacco smoking is assessed with reference to ecologic, cohort, and case-control studies. Seven arylamines have been classified by the International Agency for Research on Cancer: benzidine-based dyes and MOCA (4,4'-methylene bis 2-choloroaniline) were considered 'probably' carcinogenic, Group 2A, because of a high level of evidence in experimental animals; two occupational chemicals (2-naphthylamine and benzidine), one drug (Chlornaphazine), and two manufacturing processes (manufacture of auramine and magenta) were included in Group 1 on the basis of 'sufficient' evidence of carcinogenicity in humans. Occupational exposures to aromatic amines explain up to 25 percent of bladder cancers in some areas of Western countries; these estimates might be higher in limited areas of developing countries. Aromatic amines contaminate the ambient air as a component of environmental tobacco smoke. There is increasing evidence that the excess of bladder cancer in smokers is attributable to aromatic amines rather than to other contaminants of tobacco smoke such as polycyclic aromatic hydrocarbons (PAH). A modulating role in the risk of bladder cancer associated with exposure to aromatic amines is played by metabolic polymorphisms, such as the N-acetyltransferase genotype, raising important social and ethical issues. The consistent observation of a difference between men and women in bladder cancer risk, after allowing for known risk factors, suggests consideration of gender-related biological determinants for future investigation.