Prospective association between use of electronic cigarettes and use of conventional cigarettes: a systematic review and meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the association between e-cigarette use and subsequent initiation or recurrence of cigarette smoking. DATA SOURCES: A systematic literature search was finalised on 11 November 2019 using PubMed (including MEDLINE), EMBASE, Cochrane Library, Scopus, PubMed Health, NICE Evidence Search, PROSPERO, CRD and PsycInfo. STUDY SELECTION: Studies were included if meeting the following criteria: reporting empirical results; longitudinal observational design with a minimum of 3 months of follow-up; including general population samples; allowing for the comparison between users and nonusers of e-cigarettes. Studies rated as having high risk of bias were excluded. Studies were independently assessed by at least two authors. The procedures described by PRISMA were followed, and the quality of evidence was rated using GRADE. DATA SYNTHESIS: 30 longitudinal studies from 22 different cohorts assessing e-cigarette use among nonsmokers or never-smokers at baseline, and subsequent use of cigarette smoking at follow-up, were included in this review. A random-effects meta-analysis based on 89 076 participants showed a pooled unadjusted odds ratio (OR) of cigarette smoking among baseline nonsmoker e-cigarette users compared with nonusers of 4.68 (CI 3.64-6.02), while the adjusted OR was 3.37 (CI 2.68-4.24). These results were consistent irrespective of whether the outcome was measured as ever-smoking or as past 30-day smoking. The evidence was graded as moderate. CONCLUSIONS: Use of e-cigarettes may predict the initiation or recurrence of cigarette smoking.

Intravesical BCG treatment causes a long-lasting reduction of recurrence and progression in patients with high-risk non-muscle-invasive bladder cancer.

PURPOSE: To analyse if BCG treatment leads to long-term reduction of recurrence, progression, and cancer-specific mortality (CSM) in patients with high-risk NMIBC. MATERIALS AND METHODS: 140 patients with high-risk NMIBC were drawn from a population-based cohort of 538 patients with newly diagnosed bladder cancer in the Stockholm County between 1995 and 1996. Data were collected prospectively, and a final follow-up for recurrence, progression, and CSM was performed after 15 years. Patients that received BCG were compared with patients who did not receive BCG. Survival analysis was done with Kaplan-Meier estimates and Mantel-Cox log-rank test. Multivariable Cox proportional regression with stepwise selection was performed to verify the statistical significance of clinicopathological factors of prognostic importance. Results were displayed in Hazard ratios and a p < 0.05 was considered to be statistically significant. RESULTS: With a median follow-up of 100 months (2-182), 76 patients recurred; 50 progressed to muscle invasion; and 92 died of whom 38 died from bladder cancer. After 15-year follow-up, there was a statistically significant reduction in rate for recurrence (HR 0.40, p < 0.0001) and progression (HR 0.52, p = 0.038), but not for CSM, in patients that received BCG compared to those who did not. CONCLUSIONS: In this group, BCG in high-risk NMIBC patients reduced the long-term risk of recurrence and progression. The effect on CSM is yet to be clarified.

FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib-mediated cytotoxicity.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin-V and PI and 4',6-diamidino-2-phenylindole-staining of nuclei. In addition, signs of both caspase-dependent and - independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly-ADP ribose polymerase-cleavage as well as translocation of Apoptosis-inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3-II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC.

Outcome after BCG treatment for urinary bladder cancer may be influenced by polymorphisms in the NOS2 and NOS3 genes.

PURPOSE: Bacillus Calmette-Guérin (BCG)-treatment is an established treatment for bladder cancer, but its mechanisms of action are not fully understood. High-risk non-muscle invasive bladder-cancer (NMIBC)-patients failing to respond to BCG-treatment have worse prognosis than those undergoing immediate radical cystectomy and identification of patients at risk for BCG-failure is of high priority. Several studies indicate a role for nitric oxide (NO) in the cytotoxic effect that BCG exerts on bladder cancer cells. In this study we investigated whether NO-synthase (NOS)-gene polymorphisms, NOS2-promoter microsatellite (CCTTT)n, and the NOS3-polymorphisms-786T>C (rs2070744) and Glu298Asp (rs1799983), can serve as possible molecular markers for outcome after BCG-treatment for NMIBC. MATERIALS AND METHODS: All NMIBC-patients from a well-characterized population based cohort were analyzed (n=88). Polymorphism data were combined with information from 15-years of clinical follow-up. The effect of BCG-treatment on cancer-specific death (CSD), recurrence and progression in patients with varying NOS-genotypes were studied using Cox proportional hazard-models and log rank tests. RESULTS: BCG-treatment resulted in significantly better survival in patients without (Log rank: p=0.006; HR: 0.12, p=0.048), but not in patients with a long version ((CCTTT)n ≧13 repeats) of the NOS2-promoter microsatellite. The NOS3-rs2070744(TT) and rs1799983(GG)-genotypes showed decreased risk for CSD (Log rank(TT): p=0.001; Log rank(GG): p=0.010, HR(GG): 0.16, p=0.030) and progression (Log rank(TT): p<0.001, HR(TT): 0.05, p=0.005; Log rank(GG): p<0.001, HR(GG): 0.10, p=0.003) after BCG-therapy compared to the other genotypes. There was also a reduction in recurrence in BCG-treated patients that was mostly genotype independent. Analysis of combined genotypes identified a subgroup of 30% of the BCG-treated patients that did not benefit from BCG-treatment. CONCLUSIONS: Our results suggest that the investigated polymorphisms influence patient response to BCG-treatment and thus may serve as possible markers for identification of BCG-failures.

Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer.

Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR) = 4.93, 95% CI = 2.72-8.92, p < 0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p < 0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR = 2.15, 95% CI = 1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR = 3.68, 95%CI = 1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target.

Polymorphisms In The Nitric-Oxide Synthase 2 Gene And Prostate Cancer Pathogenesis.

BACKGROUND: Nitric-oxide synthase (NOS)-polymorphisms influence the cellular amount of NO, and are associated with disease-risk in many disorders. We investigated 145 SNP-polymorphisms and a (CCTTT)n-microsatellite in the NOS2-gene in 3161 prostate-cancer patients and 2149 controls from a Swedish population-based GWAS-study. AIM: To analyze possible associations between NOS2-polymorphisms, prostate cancer, and prostate cancer pathogenesis. METHODS: Two groups were analyzed, those with advanced tumours (Gleason≥6), and those with tumours of mixed Gleason-statues. Affymetrix 5.0-chip (SNP-polymorphisms), DNA Fragment-analysis and Sequencing ((CCTTT)n-microsatellite) were used for genotyping. Genotypes were combined with information on tumour stage, Gleason, PSA, metastases and cancer-specific death, using clinical follow-up. RESULTS: We divided the (CCTTT)n-alleles into short (S, n≤10), intermediate (M, n=11-12) and long (L, n≥13). Patients homozygous for longer repeats (LL) had decreased risk of highly aggressive (Gleason ≥7;PSA>20;T3+) tumours (OR:0.40;CI:0.14-1.08;p=0.071), but, once ill they showed a threefold increased risk of dying in prostate cancer (HR:3.31;CI:0.85-12.85;p=0.084), compared to SS-homozygotes. The SNP-alleles that co-varied with the (CCTTT)l-allele also had lower risk of aggressive tumours, as well as, once ill, a 2-4 times higher risk of dying (p=0.009). Also the proportion of patients with lymph node metastases increased with length of the (CCTTT)n-alleles of the patients (SS

Secondary stimulation from Bacillus Calmette-Guérin induced macrophages induce nitric oxide independent cell-death in bladder cancer cells.

The anti-tumour mechanisms following Bacillus Calmette-Guérin (BCG) treatment of bladder-cancer remain largely unknown. Previous studies have shown involvement of nitric-oxide (NO) formation in the BCG-mediated effect. We analyzed the effects of macrophage secreted factors (MSFs) from BCG-stimulated RAW264.7 cells on the bladder-cancer cell line MBT2. Direct treatment with BCG did not induce NO in MBT2-cells whereas supernatant from BCG-stimulated macrophages increased NOS2 mRNA and protein expression, NO concentrations and cell-death. Blocking NO-synthesis with the NOS-inhibitor L-NAME did not affect levels of cell-death suggesting cytotoxic pathways involving other signalling molecules than NO. Several such candidate genes were identified in a microarray.

The (CCTTT)n microsatellite polymorphism in the NOS2 gene may influence lung cancer risk and long-term survival, especially in non-smokers.

We analyzed the associations of the NOS2 (CCTTT)n promoter polymorphism to lung cancer risk and tumor histology in smokers and non-smokers. We also investigated lung cancer long-term survival in relation to the polymorphism, smoking data, histology, age at diagnosis, and gender. One hundred eighty-five lung-cancer patients and 164 matched controls, where non-smokers were enriched among the lung cancer cases, were genotyped by fragment analysis and sequencing. Genotypes were combined with information on histology, patient smoking status, and cancer-specific death, using a 20-year follow-up. We divided the (CCTTT)n alleles into short (n ≤ 10), intermediate (n = 11-12), and long (n ≥ 13). Patients homozygous for short repeats had significantly increased risk of lung cancer (p = 0.030) compared to carriers of two long alleles (LL). Lack of long allele was associated with a significantly increased lung cancer risk overall (p = 0.011), especially among non-smokers (p = 0.001). A significantly higher lung cancer survival was seen in non-smokers compared to smokers (p = 0.046) and in low-dose smokers compared to high-dose smokers at the time of diagnosis (p = 0.028). Moreover, non-smoking patients with squamous cell carcinoma (p = 0.015) or adenocarcinoma (p = 0.024) showed a significantly lower survival compared to other lung carcinomas. Nitric oxide can induce proliferation as well as apoptosis depending on cellular context. Our results suggest that the (CCTTT)n NOS2 microsatellite may influence the risk of developing lung cancer, especially in non-smokers, possibly by affecting intracellular nitric oxide levels. Our results also give additional information about the yet poorly understood etiological and prognostic differences between lung cancer in non-smokers and smokers.

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism.

The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions -124 and -146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

Polymorphisms in nitric-oxide synthase 3 may influence the risk of urinary-bladder cancer.

Nitric oxide (NO) is an important biological messenger known to influence several types of human cancers. NO formation is catalyzed by three different nitric oxide synthase (NOS) enzymes. In this study we analyzed if the NOS3 promoter polymorphism -786T>C (rs2070744) and the NOS3 Glu298Asp polymorphism in exon 7 (rs1799983) influence risk and pathogenesis of urinary-bladder cancer. Allelic discrimination and DNA sequencing were used to determine the -786T>C and the Glu298Asp NOS3 genotypes in 359 urinary-bladder cancer patients, from a population-based patient material, and 164 population controls. Patient genotypes were combined with information on tumor stage, grade, stage and grade progression and cancer-specific death, using a 5-year clinical follow-up. A threefold increased odds ratio for bladder cancer was found in homozygous carriers of the C allele of the -786T>C promoter polymorphism (p=0.017). No increased bladder cancer risk was found for the Glu298Asp polymorphism, but there was an association between the Glu298Asp and tumor grade (p=0.040). Our results suggest that the NOS3 promoter polymorphism -786T>C may influence bladder cancer risk.

Ser608Leu polymorphisms in the nitric oxide synthase-2 gene may influence urinary bladder cancer pathogenesis.

OBJECTIVE: The aim of this study was to analyse whether the exonic Ser608Leu (rs2297518) polymorphism in nitric oxide synthase-2 (NOS2) influences urinarybladder cancer risk and pathogenesis. MATERIAL AND METHODS: Genotyping of 359 bladder cancer patients from a population-based cohort and 164 population controls was carried out by allelic discrimination and sequencing. Genotypes were combined with information on tumour stage, grade, stage progression and cancer-specific death, from a 5-year clinical follow-up. RESULTS: For the Ser608Leu polymorphism, TT homozygotes had three-fold higher odds for bladder cancer (p = 0.081), but once ill, a lower risk for stage progression (p = 0.031) and a better prognosis. CONCLUSIONS: The data indicate that the Tallele of the NOS2 Ser608Leu polymorphism is an initial risk factor for developing urinary bladder cancer. Among bladder cancer patients, however, individuals who are TT homozygous have a lower risk of developing muscle-invasive disease and a higher cancer-specific survival. Depending on the cellular context, nitric oxide can induce proliferation as well as apoptosis. The results from this and previous studies suggest that NOS2 polymorphisms may influence both the risk of contracting bladder cancer and the aggressiveness of the disease.

The (CCTTT)n microsatellite polymorphism in the nitric oxide synthase 2 gene may influence bladder cancer pathogenesis.

PURPOSE: We analyzed whether the NOS2 promoter microsatellite (CCTTT)n polymorphism influences bladder cancer pathogenesis. MATERIALS AND METHODS: We genotyped 359 patients with bladder cancer in a population based cohort and 164 population controls by DNA fragment analysis and sequencing. Genotypes were combined with information on tumor stage, grade and stage, grade progression and cancer specific death. Clinical followup was 5 years. RESULTS: We divided (CCTTT)n alleles into short-10 or fewer, intermediate-11 or 12 and long-13 or greater repeats. Patients homozygous for 13 or longer (CCTTT)n repeats were at decreased odds ratio for bladder cancer (p = 0.010). However, after illness developed they were at 3-fold increased hazard ratio for stage progression (p = 0.062) and 4-fold increased hazard ratio for death from bladder cancer (p = 0.056). We discovered what is to our knowledge a previously undescribed polymorphism at position 23105343 (C/T). There was no difference in frequency between bladder cancer cases and population controls for this polymorphism. No associations were found between tumor stage, grade or stage and grade progression. However, patients with bladder cancer with the heterozygous CT genotype were at 3-fold increased hazard ratio of death from cancer (p = 0.011). CONCLUSIONS: Nitric oxide can induce proliferation or apoptosis depending on the cellular context. Results suggest that the (CCTTT)n NOS2 microsatellite may influence bladder cancer risk and aggressiveness. This polymorphism may have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels.

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.

We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).

Influence of DNA repair gene polymorphisms on the initial repair of MMS-induced DNA damage in human lymphocytes as measured by the alkaline comet assay.

We have applied the alkaline comet assay to study the functional impact of gene polymorphisms in base excision repair (APEX1 Asp148Glu, XRCC1 Arg194Trp, XRCC1 Arg399Gln) and homologous recombination repair (XRCC3 Thr241Met, NBS1 Glu185Gln), two pathways that play crucial roles in the repair of DNA damage induced by methylmethane sulphonate (MMS). We also examined the effect of polymorphisms in mismatch repair (MLH1 -93 A/G) and nucleotide excision repair (XPD Lys751Gln) as putative negative controls based on the limited roles of these pathways in MMS-induced repair. Phytohemagglutinin-stimulated peripheral lymphocytes from 52 healthy individuals were treated with MMS and allowed to repair for 0, 15, 40, or 120 min after a 6-min washing step. DNA damage was measured as a pseudo-percentage score (comparable to % tail DNA) converted from a total visual score calculated from the distribution of cells with different degrees of damage (normal, mild, moderate and severe). The repair was faster at the beginning of the observation period than towards the end, and was not complete after 2 hr. Presence of the APEX1 148Asp, XRCC3 241Met or NBS1 185Gln alleles were significantly associated with a high pseudo-percentage score (above median) at early time points, with the APEX1 effect being most prolonged (up to 40 min after washing, odds ratio 5.6, 95% confidence interval 2.0-15.5). No significant effects were seen with the XRCC1 Arg194Trp, XRCC1 Arg399Gln, MLH1 -93A/G and XPD Lys751Gln polymorphisms. Our results provide evidence for the functional nature of the variant alleles studied in the APEX1, XRCC3, and NBS1 genes.

Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate.

OBJECTIVES: To identify effect modification produced by genetic traits found in metabolic enzymes, to investigate how these affect the levels of different biomarkers of sprayed and thermo-degraded polyurethane (PUR) based on 4,4'-diphenylmethane diisocyanate (MDI) and to determine how associated respiratory disorders are affected. METHODS: Two partly overlapping groups of 141 and 158 factory employees exposed to sprayed or heated MDI-PUR glue were examined in years 0 and 2, respectively, for occurrence of polymorphisms in five genes (N-acetyltransferase NAT2 and the glutathione S-transferases GSTM1, GSTM3, GSTP1 [codon 105 and 114] and GSTT1) on the basis of the polymerase chain reaction, exposure biomarkers in plasma and urine (P- and U-MDX), by means of gas chromatography-mass spectrometry, specific serum IgG antibodies against MDI (S-IgG-MDI) by means of ELISA, total S-IgE, symptoms in the eyes, nose and lower airways as assessed by questionnaire and interview, and lung function as measured by spirometry. RESULTS: Both the GSTP1 (105) isoleucine/isoleucine and GSTP1 (114) alanine/alanine genotypes showed higher levels of U-MDX than the other genotypes and the GSTP1 (114) genotype modified the P-MDX/U-MDX relationship. GSTP1 (105) isoleucine/isoleucine was found to be associated with lower levels of S-IgG-MDI and fewer eye symptoms, but with an increased risk of symptoms in the airways, as well as with atopy. Presence of the GSTT1 gene resulted in somewhat lower lung function levels than did the null genotype. A slow NAT2 acetylating capacity was associated with lower P- and U-MDX and S-IgG-MDI levels, and better lung function, but a higher risk of eye and airway symptoms. Analysing the effects of combinations of the different genes provided no further information. CONCLUSIONS: Although our study has clear limitations, it reveals various effect modifications produced by the GST and NAT2 genotypes. Gene-environment interactions are highly complex. Further research is needed to obtain a more comprehensive understanding of them.

Polymorphisms in NQO1 and the clinical course of urinary bladder neoplasms.

OBJECTIVE: Urinary bladder neoplasms differ considerably in biological potential, and tumor morphology alone cannot predict their clinical behaviors. Polymorphisms in xenobiotic metabolic genes reportedly modulate susceptibility to bladder neoplasms and may affect the clinical course and outcomes of the disease. This study was conducted to determine the effect of polymorphisms in the xenobiotic metabolic genes on the disease course and clinical outcomes of urinary bladder neoplasms. MATERIAL AND METHODS: Patients with urinary bladder neoplasms who had been followed up for a 5-year period were genotyped for NQO1 (R139W, P187S), NAT (rapid/slow), GSTP1 (I105V), GSTT1 and GSTM1 (non-null/null) and MTHFR (A222V, E429A) polymorphisms. RESULTS: Variant allele carriers of the NQO1 (P187S) polymorphism showed a higher risk for high-stage disease than non-carriers at diagnosis [relative risk (RR)=1.4; 95% CI 1.0-1.8). A higher risk for highly malignant disease (T2+) was also observed in variant allele carriers than non-carriers of the GSTP1 (I105V) polymorphism (RR=1.6; 95% CI 1.1-2.5). NQO1 (R139W) variant allele carrier patients with intermediate malignant disease (TaG3+T1) had shorter disease-free survival than non-carriers (p=0.05). In contrast, carriers of the variant allele for the MTHFR (A222V) polymorphism had significantly longer disease-free survival than non-carriers (p=0.02). CONCLUSIONS: Our data are consistent with the notion that NQO1 polymorphisms influence the course and clinical outcomes of urinary bladder neoplasms. However, our results need to be confirmed in a large study as most of the associations detected were only of marginal statistical significance, and would be lost on correction for multiple comparisons.

Polymorphisms in the DNA repair genes XRCC1, APEX1, XRCC3 and NBS1, and the risk for lung cancer in never- and ever-smokers.

This case-control study examines the association between lung cancer and genetic polymorphisms in two base excision repair (BER) genes, XRCC1 and APEX1 and two genes involved in homologous recombination repair (HR), XRCC3 and NBS1. Never-smoking lung cancer patients were recruited, and also the next diagnosed ever-smoking case of the same gender and age group. Controls were recruited from the regional population register, frequency matched to cases by hospital catchment area, gender, age group and smoking category. As a result more than 70% of the study population were women. A total of 331 individuals were analysed. Presence of the XRCC1 399Gln allele was associated with a significantly decreased risk for lung cancer among non-smoking women (odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2-0.9). No significant effect was seen with the APEX1 polymorphism. Women smokers carrying the XRCC3 241Met allele showed a significantly decreased risk for lung cancer (OR 0.3, CI 0.2-0.7). The NBS1 185Gln allele was significantly associated with an increased risk for lung cancer among non-smoking women (OR 2.2, CI 1.0-4.8) and low-dose smoking women (OR 4.8, CI 1.5-15.7). The protective effect of the variant XRCC3 241Met allele was strengthened when combined with the low-risk Glu185 allele of the NBS1 gene. Smokers (OR 0.38, CI 0.16-0.90) and women (OR 0.42, CI 0.21-0.85) with at least three low-risk alleles in these two HR genes showed a significantly decreased risk for lung cancer. Thus, in spite of a relatively small study population, this study, including a comparatively large number of never-smokers and women, presents several novel aspects on genetic susceptibility to lung cancer. Our results show that the genetic variation in XRCC1, XRCC3 and NBS1 influence lung cancer susceptibility among women, and that combinations of risk alleles in the two HR genes can enhance the effects.

Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours.

We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.