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Objective: Genome-wide association studies have confirmed association of TP63C/T rs710521, TERTC/T rs2736098, and SLC14A1C/T rs17674580 gene variants with susceptibility to bladder cancer (BC) in European and White population. However, the risk conferred for BC for above gene variants in North Indians is unknown. We therefore, studied the association of TP63C/T, TERTC/T, and SLC14A1C/T single nucleotide polymorphisms (SNPs) with a risk of BC susceptibility in North Indian cohort., Material and Methods: In histologically confirmed 225 BC cases and 240 healthy controls, 3 SNPs were genotyped by real-time polymerase chain reaction. To evaluate the SNP effects on BC susceptibility, odds ratio (OR) and CI 95% were calculated., Results: In case of TP63C/T, the variant genotype (TT) showed significant reduced risk for BC (P = 0.045, OR = 0.53). Combining heterozygous and variant genotypes also demonstrated reduced risk for BC (P< 0.001, OR = 0.54). In case of TERTC/T, heterozygous genotype (CT) as well as variant genotype (TT) showed significant risk for BC susceptibility (P = 0.031, OR = 1.77 and P = 0.004, OR = 2.78, respectively) along with T allelic level (P<0.001, OR = 4.19). Furthermore, in case of SLC14A1C/T gene polymorphism, the variant genotype (TT) showed significant high risk for BC susceptibility (P = 0.006; OR = 3.01) along with variant T allelic level (P = 0.003, OR = 1.52). Interestingly, smoking was also found to modulate risks for BC in case of TERT and SLC14A1 variant genotype (TT). Further clinical confounding factor, namely, tumor grade/stage level of cases, supports the genotypic data with TERT and SLC14A1 showing a risk for BC susceptibility., Conclusion: Our results suggested that polymorphism in TERTC/T and SLC14A1C/T confirmed high risk for BC in North Indian population. However, TP63C/T showed reduced risk of BC susceptibility. More replicate studies with large sample size and diverse ethnicity are required to validate these observations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chemokines are small inducible pro-inflammatory cytokines. In the present study, we tested association of chemokine single nucleotide polymorphisms (SNPs) viz., CCR5∆32, CXCL12G801A and CXCR2C1208T genes in bladder cancer (BC) patients and normal healthy controls of north Indians. Genotyping of the above SNPs were done in 200 BC cases and 200 healthy controls, using RFLP and amplification refractory mutation system-polymerase chain reaction methodology. A significant association was found in CXCL12G801A with BC risk. In case of CXCL12G801A polymorphism, the heterozygous (GA) genotype showed significantly high risk (p < 0.001, odds ratio (OR) = 2.72), whereas A allele carrier (GA + AA) also showed risk with BC (p < 0.001, OR = 2.44). In CXCR2C1208T polymorphism, the variant genotype (TT) showed significant risk for BC (p = 0.028, OR = 1.58). The variant allele (T) of CXCR2C1208T polymorphism was found to be associated with BC risk (p = 0.003, OR = 1.29). Interestingly, smoking was also found to modulate 1.16-fold risks for BC in case of CXCR2C1208T, variant genotype (TT). Upon analyzing the gene-gene interaction between CXCR2C1208T and CXCL12G801A, the combination CT-GA showed 4-fold risk for BC (p = 0.009). Our results indicated that polymorphism in CXCR2C1208T and CXCL12G801A showed high risk for BC in north Indian population. However, CCR5∆32 exhibited no association. Study with large sample size and diverse ethnicity are required to validate these observations.

Cytotoxic T Lymphocyte antigen 4 (CTLA4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T cell activation. We examined candidate disease-susceptibility single nucleotide polymorphism (SNPs) of CTLA4 at +49A/G, CT60A/G and -318C/T genes in bladder cancer (BC) patients of North Indian population. Histopathologically confirmed 200 patients of BC and 200 unrelated, healthy controls of similar ethnicity were genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation specific (PCR-ARMS) methods. In present study SNP CTLA4 +49A/G, variant genotype showed 3.74-fold risks for BC. While looking at G allele carrier level, risk for BC was high (OR = 1.54). The risk for BC was also evident in case G allele (OR = 1.58). CTLA4 CT60A/G gene polymorphism variant genotype showed 1.36-fold risks for BC. While at G allele carrier and with variant G allele it showed significantly reduced risk for BC. CTLA4 +49A/G genotype exhibited 1.57-fold risks with smoking in BC patients in homozygous mutant condition. In silico analysis further supports the results of SNP at CTLA4 +49A/G and CTLA4 CT60A/G. None of the above SNPs of CTLA4 demonstrated association with tumor stage/grade for BC severity and progression. BCG immunotherapy had no impact on CTLA4 gene polymorphism revealing no significant association. Haplotype GAC showed high risk for BC while other haplotype AGT showed reduced risk for BC. Our results indicated that genetic variations in CTLA4 gene (+49A/G, CT60A/G) play role in susceptibility to BC. Haplotype GAC showed high risk for BC. An association study utilizing a larger sample size and different ethnicity warrant further investigation through replication and advance techniques.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific potent mitogen involved in a number of pathologic processes, including angiogenesis, tumor growth, and metastasis. Polymorphisms of VEGF gene have been associated with susceptibility to several cancers. VEGF gene susceptibility to bladder cancer (BC), however, still remains controversial. We analyzed association of the -2578C/A, -7C/T, -2549I/D, and -1001G/C polymorphism of the VEGF gene with bladder cancer (BC) risk and interaction of these polymorphisms with lifestyle and demographic factors. We genotyped -2578C/A, -7C/T, -2549I/D and -1001G/C by PCR-restriction fragment length polymorphism and amplification refractory mutation specific method to evaluate risk in 200 BC patients and 250 healthy controls from North Indian population. Significant association for BC risk in heterozygous CA genotype (1.69-fold) in VEGF-2578C/A and heterozygous genotype of VEGF-1001G/C (p = 0.032) was observed. Interestingly, VEGF-2549I/D genotype showed reduced risk for BC. The gene-gene combination analysis revealed DD-GG with reduced risk (p = 0.018) of VEGF-2549I/D and VEGF-1001G/C, and combination CA-GG of VEGF-2578C/A and VEGF-1001G/C demonstrated 1.75-fold risk for BC. Our findings suggested that polymorphism -2578C/A and -1001G/C in the promoter of VEGF gene may play a significant role in mediating the bladder cancer risk, whereas VEGF-2549I/D genotype appears to be protective for BC.

IL-12 and IL-18 are immunomodulatory cytokines that play important roles in host immune response against cancers. Variation in DNA sequence in gene promoter may lead to altered IL-18 production and/or activity, and hence can modulate an individual's susceptibility to BC. To test this hypothesis, we investigated the relationship of IL-18 gene promoter -137 G/C and -607C/A polymorphisms and IL12 (-16974) A/C with the risk of BC in North Indian population. Polymorphisms in IL-18 and IL-12 genes were analyzed in 200 BC patients and 200 age, ethnicity and sex-matched controls, using restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) and amplification refractory mutation specific-polymerase chain reaction (ARMS) method. The concentrations of IL-18 in serum were determined by ELISA. Significant association was observed with IL18 (-137) G/C heterozygous genotype (GC) with 1.96 folds risk of BC as well at C allele carrier and variant C allele having 2 fold and 1.6 fold risk for BC respectively. IL18 (-607) C/A, heterozygous CA genotype also showed a high risk (OR=1.59) for BC. While IL12 (-16974) A/C heterozygote genotype and C allele carrier demonstrated reduced risk of BC. Hetero genotype of IL18 (-137) G/C was associated with risk of recurrence (HR=2.35) in superficial BC patients receiving BCG treatment thus showing least survival. The distributions of IL-18 gene haplotypes were not significantly different between patients and controls. Serum IL-18 levels were significantly higher in BC patients than in the healthy subjects (p=0.025). Serum IL-18 levels was also significantly associated with IL18 (-137) G/C in heterozygous genotype (GC) (p=0.048). Our results suggest that IL-18 gene polymorphism contributes to bladder cancer risk whereas IL-12 is protective. A relation between IL18 (-137) G/C in heterozygous genotype with elevated IL-18 serum level and bladder cancer risk has been registered in the present study., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Aims: Impairment of the immune system may contribute to the risk for having cancer as Toll-like receptors are important for innate immunity. We examined the association between candidate disease-susceptibility polymorphisms in the single nucleotide polymorphism (SNPs) like TLR2 (-196 to-174del), TLR3 (C1377T), TLR4 (Thr399Ile) and TLR9 (G2848A) genes in patients with bladder cancer in a North Indian population., Methods: SNPs were comprised of TLR2 (-196 to -174 Del), TLR3(C1377T), TLR4 (Thr399Ile) and TLR9 (G2848A) genes. Allelic and genotypic frequencies of these TLRs SNP from histopathologically confirmed patients of bladder cancer (n = 200) and unrelated healthy controls of similar ethnicity (n = 200) were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis., Results: In TLR2 I/D gene polymorphism, the combination of ID+DD showed a significant 3-fold increased risk (p = 0.001). TLR2 with heterozygous genotype ID showed a 3-fold risk and combination of heterozygous and variant genotype (ID+DD) also showed a 5-fold risk with tumor stage/grade of patients with bladder cancer. The other genotypes of TLR3, 4 and 9 did not exhibit any significant association with bladder cancer risk., Conclusions: Our results suggested the involvement of TLR2 (-196 to-174 del) in bladder cancer susceptibility; however, TLR3, 4 and 9 genes were not associated with risk of bladder cancer, implicating that polymorphisms in these tested TLRs genes are not likely to be associated with increased risk for developing bladder cancer. Functional studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in identifying the disease-associated variants for the etiology of bladder cancer., (Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.)

Chemokine genes have been proposed as good candidate genes for conferring susceptibility to Bladder cancer (BC). We examined the combined effect of multiple alleles of pro inflammatory chemokine genes for determining the risk of BC. We tested association of three gene polymorphisms of CCL2I/D (rs3917887), CCL2A2518G (rs1024611) and CCR2V64I (rs1799864) with BC risk in North Indian population. Genotypes were assessed in hospital-based case-control study comprising of 200 BC patients and 200 healthy controls. Genomic DNA was isolated from blood and genotyping done using PCR-RFLP method. In CCL2I/D polymorphism, the heterozygous genotype (I/D) showed high risk of BC p < 0.001 OR = 2.56 and combination of ID + DD showed significant high risk for BC (p = 0.001 OR = 2.12). Haplotype analysis of CCL2I/D, CCL2A2518G gene polymorphisms demonstrated that combination of D-A was associated with 1.5-fold increased risk of BC. Variant genotype (DD) of CCL2I/D gene was associated with high risk of recurrence (p < 0.001 HR = 15.18) in superficial BC patients receiving BCG treatment thus showing least survival (log rank = 0.019). Our study suggested CCL2I/D polymorphism to be associated with higher BC risk and no contribution of CCR2V64I and CCL2A2518G genes. However, study with large sample size and diverse ethnicity is required to validate our observations.

There is a considerable discrepancy between the number of identified occupational-related bladder cancer cases and the estimated numbers particularly in emerging nations or less developed countries where suitable approaches are less or even not known. Thus, within a project of the World Health Organisation Collaborating Centres in Occupational Health, a questionnaire of the Dortmund group, applied in different studies, was translated into more than 30 languages (Afrikaans, Arabic, Bengali, Chinese, Czech, Dutch, English, Finnish, French, Georgian, German, Greek, Hindi, Hungarian, Indonesian, Italian, Japanese, Kannada, Kazakh, Kirghiz, Korean, Latvian, Malay, Persian (Farsi), Polish, Portuguese, Portuguese/Brazilian, Romanian, Russian, Serbo-Croatian, Slovak, Spanish, Spanish/Mexican, Tamil, Telugu, Thai, Turkish, Urdu, Vietnamese). The bipartite questionnaire asks for relevant medical information in the physician's part and for the occupational history since leaving school in the patient's part. Furthermore, this questionnaire is asking for intensity and frequency of certain occupational and non-occupational risk factors. The literature regarding occupations like painter, hairdresser or miner and exposures like carcinogenic aromatic amines, azo dyes, or combustion products is highlighted. The questionnaire is available on www.ifado.de/BladderCancerDoc.

Survivin is a member of novel inhibitor of apoptosis protein family which expressed in human cancers. The molecular detection of bladder cancer by targeting Survivin as a novel marker may be useful in the occurrence and progression of cancer. We genotyped Survivin -31G>C, -1547A>G and -241C>T by PCR-restriction fragment length polymorphism to evaluate the risk of bladder cancer (BC) in 200 BC patients and 200 healthy controls from North Indian cohort. We observed significant increased BC risk associated with variant CC genotype of Survivin -31G>C having 2.6 fold risk. The variant genotype of Survivin -1547A>G was significantly associated with BC risk (P = 0.047). In case of Survivin -241C>T the protective genotype for BC was heterozygous (P = 0.035). Smoking significantly modulated the risk in patients with Survivin -1547A>G polymorphism. Variant as well as hetero genotype of Survivin -31G>C was associated with reduced risk of recurrence (HR = 0.22 and 0.35) in BC patients receiving BCG treatment thus showing least survival. Furthermore, the haplotype analysis revealed C-A-T haplotype to be associated with reduced BC risk. Our findings suggested that the functional polymorphism -31G>C, -1547A>G and -241C>T in the promoter of Survivin gene may play a significant role in mediating the BC risk among North Indian cohort.

Purpose: Carcinogens causes DNA damage, including oxidative lesions that are removed efficiently by the base excision repair (BER) pathway. Variations in BER genes may reduce DNA repair capacity, leading to development of urological cancers., Methods: This study included 195 prostate cancer (PCa) and 212 bladder cancer (BC) patients and 250 controls who had been frequency matched by age, sex, and ethnicity. We genotyped XRCC1 Exon 6 (C>T), 9 (G>A), 10 (G>A), OGG1 Exon 7 (C>G) and APE1 Exon 5 (T>G) genes polymorphism using PCR-RFLP and ARMS., Results: GA of XRCC1 Exon 9 demonstrated increased risk with PCa as well as in BC (p=0.001; p=0.006). Similarly variant containing genotype revealed association with PCa (p=0.031). Haplotype of XRCC1 also associated with significant risk for PCa and BC. The APE1 GG genotype showed a decreased risk of BC (OR=0.25; p=0.017). Variant genotype GG of OGG1 demonstrated significant risk with BC (p=0.028)., Conclusions: Our observations suggested increased risk for PCa and BC in case of GA genotype for XRCC1, and variant GG in case of OGG1. However APE1 GG genotype conferred a protective association with BC susceptibility. Larger studies and the more SNPs in the same pathway are needed to verify these findings., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The DNA double strand break repair gene XRCC4, an important caretaker of genome stability and XRCC3 are suggested to play an imperative role in the development of carcinogenesis. However, no evidence has been provided showing that these genes are associated with risk of urinary bladder cancer (UBC). The study was designed to examine the polymorphisms associated with two genes namely XRCC4 G1394T (rs6869366), intron 3 (rs28360317), intron 7 rs1805377 and rs2836007 and XRCC3 (rs861539 and rs1799796), respectively and investigate their role as susceptible markers for UBC risk in North Indian cohort. In this hospital-based case-control study histologically confirmed 211 UBC patients and 244 age and gender matched controls of similar ethnicity were genotyped by means of PCR-RFLP. Significant different distributions in the frequency of the XRCC4 intron 3 genotype, but not the XRCC4 G1394T or intron 7 genotypes, between the UBC and control groups were observed. XRCC4 intron 7 Del/Del conferred enhanced risk (OR 1.94; P 0.017) in UBC. Interestingly, XRCC -1394 G>T variant genotype GG was associated with reduced risk (OR 0.27; P 0.020). However, none of the four polymorphisms in XRCC4 were associated with tobacco smoking and risk of recurrence in patients treated with BCG immunotherapy. Similarly, none of the XRCC3 polymorphisms were associated with UBC susceptibility. Our results suggested that the XRCC4 intron 3 rs6869366 genotype and intron 7 rs28360317 may be associated with UBC risk and may be a novel useful marker for primary prevention and anticancer intervention.

Purpose: Bladder cancer (BC) is one of the most widespread cancers afflicting men and women and also has major philosophical impact on health care worldwide. Despite elaborate characterization of the risk factors and treatment options, BC is still a major epidemiological problem worldwide and its incidence lingers to upswing each year. Over the last three decades, intravesical immunotherapy with the biological response modifier Mycobacterium bovis-Bacillus Calmette Guerin (BCG) has been established as the most effective adjuvant treatment for averting local recurrences and tumor progression following transurethral resection of non-muscle-invasive bladder cancer., Design and Methods: PUBMED database was searched for articles, and manuscripts were selected that provided data regarding the correlation of BCG therapy and its response with different cytokine gene variants., Results: It is not clear how Bacillus Calmette-Guerin (BCG) works to treat BC. It may stimulate an immune response or cause inflammation of the bladder wall that destroys cancer cells within the bladder. Lot of reports indicated the correlation of various cytokines with respect to BCG therapy in BC, but the exact mechanism is under debate., Conclusion: Research continues to establish the most effectual strain of BCG and the best dosage schedule for the treatment for bladder cancer but, on the other hand, a very critical part of this therapy to find out the correlation of different cytokine with BCG therapy, which will give a better insights not only the mechanism but also a better therapeutic options.

MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of cellular functions through post-transcriptional regulations on target genes. Common genetic variants (single-nucleotide polymorphisms, SNPs) in pre-miRNA genes may alter their expression and/or maturation effecting thousands of target mRNAs, resulting in varied functional consequences. Three common SNPs (hsa-mir-146a G>C rs2910164, hsa-mir-196a2 C>T rs11614913, and hsa-mir-499 T>C rs3746444) in pre-miRNAs were investigated to evaluate their association with urinary bladder cancer risk. The hospital-based case-control study comprised of 212 histologically confirmed patients with urinary bladder cancer and 250 healthy controls who were unrelated, of similar ethnicity, and age and gender matched. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism methodology. Our results showed that the heterozygous genotype of rs11614913 was higher in cases than controls but the results were marginally significant (p = 0.055; odds ratio, 1.44). Smoking had no impact in modulating the effect of any of the three miRNA SNPs studied. No association was observed with either the tumor stage or grade in patients with bladder cancer. Even though there was no association between the individuals carrying the variant genotypes of the three miRNA studied and bladder cancer risk, marginal significance of heterozygousity in rs11614913 suggested further characterization of miRNA SNPs in a large cohort of varied ethnicity. This could further provide new prospects for understanding the underlying mechanisms between miRNAs and disease etiology.

Background: Cyclooxygenase-2 (COX-2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of processes that are relevant to cancer development. It is involved in carcinogenesis, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. The gene for COX-2, designated as prostaglandin-endoperoxide synthase 2 (PTGS-2), carries polymorphisms, such as -765G>C, 1195G>A in the promoter region, and 8473T>C in the 3'-untranslated region (UTR), which have been associated with susceptibility to malignant disease., Methods: We undertook a case-control study of 212 urothelial bladder cancer (UBC) cases and 250 controls to investigate the association between COX-2 polymorphism and bladder cancer susceptibility, using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and also investigated gene-environment interactions., Results: Cox-2 765G>C, a variant(C) allele carrier, was at an increased risk of UBC (odds ratio [OR] = 1.90; P = .004); however, -1195G>A; -1290A>G; and 3'UTR 8473T>C polymorphisms of COX-2 gene were not significantly associated with UBC. 765G>C also was associated with the invasive stage of a bladder tumor (OR = 2.73; P = .033). High risk for UBC also was observed with respect to COX-2 haplotypes C-765T8473A-1195A-1290 (OR = 3.47; P = .014). In case-only analysis, COX-2 765 variant allele carrier genotypes also showed an increased risk among former and current smokers (OR = 3.06; P = .041 and OR = 4.39; P = .032, respectively)., Conclusion: COX-2 -765G>C polymorphism confers UBC susceptibility particularly in smokers and in patients with invasive tumors. 765C allele carrier genotypes also are influenced with a high risk of recurrence in Bacillus Calmette-Guérin-treated patients. Collectively, these findings confirm that the COX-2 -765G>C polymorphism is a risk factor for the development of bladder cancer and can provide a plausible mechanistic explanation. Further validation in large population-based studies is needed., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Perturbations in the cell cycle and apoptotic genes have been implicated in human malignancies. Cell cycle (MDM2 and Cyclin D1) and apoptotic (Fas) genes that are differentially expressed in urinary bladder cancer (UBC) were investigated with the susceptibility to UBC in northern India. A total of 212 UBC patients and age- and sex-matched 250 controls were investigated for MDM2 G309T, Cyclin D1 G870A, and Fas A670G polymorphisms by polymerase chain reaction and restriction fragment length polymorphism. MDM2 309GG was at reduced risk for developing UBC when compared with TT genotype (p = 0.027; odds ratio, 0.55). GG genotype was also associated with reduced risk in nonmuscle invasive bladder cancer (NMIBC) and muscle invasive BC (p = 0.006 and p = 0.049). Cyclin D1 AA genotype was associated with high risk in NMIBC (intermediate risk) stage (p = 0.015; odds ratio, 4.55). MDM2-Cyclin D1 interaction revealed overall protective effect. The GG genotype of MDM2 also showed a protective effect and high recurrence-free survival in Bacillus Calmette-Guerin-treated NMIBC patients (log rank p = 0.008). MDM2 GG genotype had protective effect and MDM2T309G polymorphism had profound influence in Bacillus Calmette-Guerin-treated UBC patients in the North Indian population.

Background: Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette-Guerin (BCG) immunotherapy for high risk superficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic/apyriminidic endonuclease (APEX1) gene in tumor recurrence after BCG immunotherapy in SBC patients., Materials and Methods: The study included 135 SBC patients, of which BCG immunotherapy was received by 74 patients. Genotyping was performed for ERCC2 Asp(312)Asn (G > A), Lys751Gln (A > C), and APEX1 Asp(148)Glu (T > G) polymorphisms by restriction fragment length polymorphism PCR and amplification refractory mutation system (ARMS) methods., Results: Multiple Cox regression analysis demonstrated association of variant genotype of ERCC2 (312)AA polymorphism with high risk of recurrence in BCG treated patients (HR = 3.07, P = 0.016, P ( c ) = 0.048). Patients with the ERCC2 (312)AA polymorphic genotypes showed shorter recurrence free survival (log-rank, P = 0.005; AA/GA + AA = 14/44) who received BCG treatment. Overall, risk of recurrence in bladder cancer was observed with smokers and size of tumors (1-3 cm) (HR = 1.86, P = 0.023 and HR = 3.19, P = 0.031, respectively). Smokers were identified to be at elevated risk in BCG treated patients (HR = 2.84, P = 0.005). No association was observed with the (ERCC2 Lys(751)Gln and APEX1 Asp(148)Glu) polymorphisms and risk of recurrence., Conclusion: Our data suggested variant (AA) of ERCC2 312 AA genotype to be associated with high risk of tumor recurrence and reduced recurrence free survival in superficial bladder cancer patients.

Purpose: To investigate the association between two Xeroderma pigmentosum group C polymorphism (XPC Lys939Gln and insertion/deletion PAT -/+ in intron 9) and bladder cancer (BC) susceptibility., Materials and Methods: Genotyping was performed in 208 BC patients and 245 controls by PCR-RFLP method., Results: XPC PAT +/+ genotype was associated with elevated risk of BC (p = 0.021, OR = 2.49). XPC Lys939Gln AC + CC genotype was significantly associated with risk in invasive stage of BC (p = 0.041, OR = 2.52). Haplotype analysis revealed that variant genotypes C of XPC Lys939Gln and + of PAT, C+ were significantly associated with risk of BC (p = 0.004, OR = 1.70). The CC genotype of Lys939Gln was associated with high risk for recurrence in BCG-treated patients (HR = 3.21, p = 0.036) thus, showing reduced recurrence-free survival (AC + CC/AA = 36/60 months; log rank p = 0.045)., Conclusion: Polymorphisms and haplotypes in XPC appear to influence susceptibility to BC risk. The variant C allele at Lys939Gln may be responsible for early recurrence in BCG-treated patients.

Background and Aims: Chemokines and transcription factor NF-kappaB play a pivotal role in development of carcinoma of the bladder (CaB). The present study was conducted to analyze the association of chemokines IL-8 -251 T>A and +678 C>T and NF-kappaB -94 (ATTG) insertion/deletion polymorphisms with the risk of CaB and outcome after bacillus Calmette-Guerin (BCG) immunotherapy in a cohort of northern India., Methods: Histologically confirmed 205 CaB cases and 270 controls were included. Of these, 71 patients were treated with BCG immunotherapy. Genotyping was done using allele-specific PCR methodology., Results: The variant genotype (AA) of IL-8 -251 polymorphism was associated with more than 2-fold risk of CaB (OR 2.12; p = 0.003; 95% CI 1.28-3.52). None of the other genotypes showed association with CaB risk. Subsequently, the diplotype -251A/+678T demonstrated a 1.8-fold increased risk for CaB (OR 1.84, 95% CI 1.37-2.47). Furthermore, -251 AA genotypes reduced the risk of recurrence after BCG immunotherapy (AA; HR 0.12; 95% CI 0.04-0.41). Subsequently, improved recurrence-free survival (mean recurrence-free survival for GG, GA and AA genotypes was 24, 39 and 53 months respectively). Similarly, NF-kappaB ATTG Ins/Ins genotype was at reduced risk of recurrence after BCG treatment compared to Del/Del genotype, which exhibited a 2.5-fold increased risk of recurrence in patients treated with BCG immunotherapy (HR, 2.53; 95% CI 1.00-6.36). Subsequently, mean recurrence-free survival (Ins/Ins, 41; Ins/Del, 44 and Del/Del, 10 months; log rank, 0.030)., Conclusions: Our results suggested that the IL-8 -251 T>A polymorphism may be a relevant host susceptibility factor for bladder carcinoma development and may influence outcome after BCG immunotherapy. Similarly, NF-kappaB ATTG polymorphism may also modify risk-free survival of BCG-treated patients., (Copyright 2010 IMSS. Published by Elsevier Inc. All rights reserved.)

Objective: Polymorphisms in DNA repair genes may be associated with altered DNA repair capacity, thereby influencing an individual's susceptibility to smoking-related cancers such as bladder cancer. Therefore, we sought to examine the correlation between single nucleotide polymorphisms in DNA repair genes and bladder cancer., Methodology: We undertook a case-control study of 212 urothelial bladder cancer (UBC) cases and 250 controls to investigate the association between OGG1 (C1245G rs1052133), XRCC3 (C18067T, rs861539) and XRCC7 (G6721T, rs7003908) polymorphisms and bladder cancer susceptibility by PCR-RFLP and the ARMS method. We also investigated gene-environment interactions., Results: The OGG1 GG genotype was associated with an elevated risk of urothelial bladder cancer (UBC) (OR, 2.10; p, 0.028). XRCC7 + 6721 GG was also associated with increased susceptibility to UBC (OR, 4.45; p, 0.001). In a recessive model, the OGG1 GG genotype showed an increased risk of TaG(2,3) + T1G(1-3) tumors. Additionally, the OGG1 GG genotype in non-smokers represented a 2.46-fold greater risk (OR, 2.46; p, 0.035) in bladder cancer patients. Subsequent analysis demonstrated more pronounced association of XRCC7 with smokers (OR, 4.39; p, 0.001). XRCC7 also showed increased association with TaG(2,3) + T1G(1-3) tumors and muscle invasive tumors (OR, 3.16; p, 0.001 and OR, 4.24; p, 0.001, respectively). Multiple Cox regression analysis in non-muscle invasive bladder tumor (NMIBT) patients demonstrated an association of the OGG1 GG polymorphism with a high risk of recurrence in patients on cystoscopic surveillance (HR, 4.04; p, 0.013). Subsequently, shorter recurrence-free survival (log rank p, 0.024; CC/GG, 42/24) was observed., Conclusion: Our data suggest association of a variant (GG) genotype of OGG1 with increased UBC susceptibility and a high risk of tumor recurrence in NMIBT patients on cystoscopic surveillance. XRCC7 G allele carriers (TG+GG) are also at an elevated risk for susceptibility to UBC as evidenced by a high odds ratio throughout the analysis.

Background: Dysregulation of apoptosis plays a crucial role in carcinogenesis. Our aim was to investigate the association of Caspase 9 and Caspase 8 gene polymorphism with bladder cancer (BC) susceptibility., Methods: We undertook a case-control study of 212 (BC) cases and 250 controls to investigate the association between Caspase 9-1263A > G, Caspase 9-293del, and Caspase 8-6 N ins/del polymorphism and BC susceptibility by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method, and further to study the influence on recurrence in patients after Bacillus Calmette-Guerin (BCG) immunotherapy., Results: Overall, no statistically significant association was observed in Caspase 9-293del and Caspase 8. Nevertheless, Caspase 9-1263GG genotype was at reduced risk of BC [p = 0.010; odds ratio (OR) = 0.487]. Caspase 9-1263AG genotype was also observed to be significantly associated with reduced risk with high-risk non-muscle-invasive bladder cancer (NMIBC) (TaG(2-3), T1G(1-3)) and invasive tumors (T2 +) of BC (P = 0.042, OR = 0.39 and P = 0.013, OR = 0.028 respectively). Caspase 9-293del, heterozygous (-/+) genotype, too, demonstrated protective effect in high-risk NMIBC (P = 0.017; OR = 0.205). Haplotype analysis revealed variant genotypes Caspase 9AG + GG/Caspase 8 DI + II to be at reduced risk of BC (= 0P.014, OR = 0.47). The GG genotype of Caspase 9-1263 was associated with reduced risk for recurrence in BCG-treated patients [hazard ratio (HR) = 0.217, P = 0.005], thus showing increased recurrence-free survival (log-rank P = 0.024)., Conclusion: Polymorphism in Caspase 9-1263 was observed to play a protective role in susceptibility to BC risk. Caspase 9 gene variants were also associated with reduced risk of NMBIC stages. The variant G allele at Caspase 9-1263 may be responsible for increased recurrence-free survival in BCG-treated patients.

Objectives: To explore the association between xerodema pigmentosum group D (XPD) Asp(312)Asn and Lys(751)Gln and apurinic apyrimidic endonuclease 1 (APE1) Asp(148)Glu gene polymorphism and risk of bladder cancer (BC) susceptibility., Methods: This hospital-based case-control study included 206 patients with newly diagnosed bladder transitional cell carcinoma and 250 cancer-free controls who had been frequency matched by age, sex, and ethnicity. Polymorphisms in XPD Asp(312)Asn and Lys(751)Gln and APE1 Asp(148)Glu gene using polymerase chain reaction-restriction fragment length polymorphism and amplification refractory mutation system were genotyped., Results: The XPD Asp(312)Asn AA genotype was associated with an elevated risk of BC (odds ratio [OR] 3.30, P = .001.) The AA genotype was significantly associated with nonmuscle-invasive BC (OR 4.62, corrected P = .003). Both the heterozygous GA and the homozygous AA was associated with a greater risk of low-grade (grade 1) BC (OR 2.51, corrected P = .006 and OR 5.21, corrected P = .003, respectively). The APE1 GG genotype showed a decreased risk of BC (OR 0.27, P = .027.) Haplotype AC (codon 312A-codon 751C) of XPD demonstrated an association with a greater susceptibility to BC (OR 2.16, correct P = .0008)., Conclusions: Reduced DNA repair capacity due to XPD Asp(312)Asn AA genotype might be a risk factor for BC. The AA genotype predisposed to a greater risk at the initial stage and grade of BC. The APE1 148GG genotype conferred a protective association with BC susceptibility.

Background and Aims: Interleukin-10 (IL-10) is an immunosuppressive cytokine that may promote tumor growth and metastasis in later stages of cancer development. DNA sequence variations in IL-10 gene may lead to altered production and/or activity, and this can modulate an individual's susceptibility to urothelial bladder cancer (UBC). To test this hypothesis, we investigated the association of rs 1800896 and rs 3021097 polymorphisms in IL-10 gene and their haplotypes with the risk of UBC in a Northern Indian population., Methods: We analyzed two single nucleotide polymorphisms of IL-10 gene at G-1082A (rs 1800896) and C-819T (rs 3021097) in 214 histologically confirmed UBC patients and 385 matched controls by allele-specific polymerase chain reaction (AS-PCR)., Results: IL-10 C-819T CT, TT genotypes and T carriers (CT + TT) had significant association with UBC susceptibility (OR 1.75, 95% CI 1.09-2.80; OR 1.81, 95% CI 1.09-3.01 and OR 1.77, 95% CI 1.14-2.75, respectively). Similarly, GA, AA genotypes and A carriers (G-1082A) demonstrated increased risk for UBC (OR 1.91, 95% CI 1.04-3.50; OR 2.01, 95% CI 1.08-3.74 and OR 1.95, 95% CI 1.09-3.50, respectively). TT (C-819T) and T carriers showed protective association with high-risk tumors; (OR 0.34, 95% CI 0.13-0.88 and OR 0.41, 95% CI 0.17-0.97, respectively). We did not observe any association of IL-10 polymorphisms with smoking habits and UBC risk., Conclusions: The study suggested that the low-producing genotypes of IL-10 (C-819T and G-1082A) polymorphisms are associated with increased UBC risk. Individuals with (C-819T) TT genotype and T carriers, however, showed a protective association with high-risk tumors. Our data suggest that IL-10 G-1082A and C-819T polymorphisms may be used as a molecular marker of urothelial bladder cancer.

The role of low penetrance genes and environmental factors in the etiology of bladder cancer (CaB) is unclear, but may involve genetic and environmental factors. Most environmental pro-carcinogens require metabolic activation by phase I enzymes (CYP450s), However, phase II enzyme (i.e., microsomal epoxide hydrolase: mEH) is mainly involved in the detoxification of wide variety of endogenous or exogenous carcinogens. Genetic differences in CYP1A1 gene and the mEH gene polymorphisms have been reported to be associated with susceptibility to various cancers. In our case-control study, we assess whether Msp1 polymorphism of CYP1A1 (CYP1A1*2A), and His(113) in exon 3 and Arg(139) in exon 4 of the mEH susceptibility genotypes, tobacco-use and age factors contribute to bladder cancer risk among Indians. A case-control study was conducted in 106 bladder cancer (CaB) patients and 160 age matched controls from similar ethnic background. The CYP1A1*2A and mEH genotypes were determined by polymerase chain reaction/restriction fragment length polymorphism method from DNA extracted from peripheral blood samples. Binary logistic regression model was used for assessing differences in genotype prevalence between patients and the controls. The Arlequin software package was used to compute haplotype frequencies. We observed non-significant association in T/C polymorphism of the CYP1A1 gene (CYP1A1*2A); however, the exon 3 His genotype of the mEH gene polymorphism alone (odds ratio = 2.67, P = 0.001) or in combination with tobacco-users were significantly associated with the risk of bladder cancer. No associations were observed with stage or grade of bladder tumor with these genotypes. In conclusion, our study demonstrated that exon 3 His genotype of the mEH are more prone to the risk of sporadic bladder cancer in North India.

Cytokines mediate many immune and inflammatory responses contributing to tumorigenesis. The present study evaluated polymorphisms of IL4, IL6, and TNF (previously TNFA) genes influencing risk in development of transitional cell carcinoma of bladder and recurrence after bacillus Calmette-Guérin (BCG) immunotherapy. The study included 136 unrelated histopathologically confirmed cases and 200 population-based controls. Genomic DNA was extracted from peripheral leukocytes and genotyped for polymorphism in IL4 intron 3, with point mutations identified by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) in IL6-174 G/C and by PCR-restriction fragment length polymorphism analysis in TNF-308 G/A. The IL6 variant C/C exhibited significant association with bladder cancer risk (odds ratio OR = 2.811, P = 0.004), but IL4 and TNF genetic variants did not. Significant association was observed for IL4 (B1/B2+B2/B2) with high-grade or late-stage tumor for TaG3+T1 and T2+ (OR = 5.950, and 6.342 respectively) and with smoking (P = 0.004, OR = 4.202). Low recurrence risk was observed in BCG-treated patients carrying C/C genotype of IL6 (hazard ratio = 0.298, P = 0.03), and also higher recurrence-free survival (log rank P = 0.021). TNF and IL4 demonstrated no association of bladder cancer risk and BCG therapy. The low-producing variant C/C of IL6 may be a risk factor for bladder cancer, whereas high-producing genotypes of IL4 (B1/B2+B2/B2) may predispose to higher risk in patients with high-grade or late-stage tumor and smoking habits. The low-producing C/C IL6 genotype, which favors Th1 response, may be a beneficial prognostic indicator for treatment and survival of BCG-treated patients.

XRCC1 protein plays crucial role in base excision repair (BER)by acting as a scaffold for other BER enzymes. Variants in XRCC1 gene might alter protein structure/function or create alternatively spliced protein influencing BER efficiency and affect individual susceptibility/recurrence to urinary bladder cancer (BC). We tested whether polymorphisms in XRCC1 gene were associated with BC risk and further to substantiate risk of recurrence after Bacillus Calmette-Guerin (BCG) immunotherapy. Genotyping for three polymorphic sites of XRCC1 gene at codon Arg194Trp (PvuII), Arg280His (RsaI) and Arg399Gln (MspI) in 140 BC cases and 190 controls by PCR-RFLP method was done. We observed significant association in heterozygous genotype (GA) of codon 280 and 399 with BC risk (OR = 1.96, p = 0.021 and OR = 1.81, p = 0.021, respectively), however no association was seen for variant AA genotype. A trend of increased risk with high stage and grade in patients with codon 194 variant genotypes (CT + TT) was observed. Haplotype analysis showed that individuals with haplotype 194C-280G-399A were at >3-fold higher risk for BC (OR = 3.48, p = 0.01). The A/A genotype of codon 399 was associated with high risk for recurrence in BCG treated patients (HR = 5.05, p = 0.01) thus, showing reduced recurrence free survival (AA/GG = 12/60 months; log rank p = 0.004). The study suggested no association of variant genotypes with the susceptibility to BC. Haplotype analysis however, revealed that XRCC1 399 A allele may have a major role as patients with haplotype 194C-280G-399A carrying variant allele of 399 were at higher risk.

Objectives: To evaluate whether polymorphism of interleukin (IL)-1beta gene (exon 5 and promoter region) and IL-1 receptor antagonist (Ra), 86-bp variable number tandem repeat, are associated with transitional cell carcinoma of the urinary bladder, because cytokines have been hypothesized to be important in cancer development., Methods: The study included 120 patients with bladder cancer (age range 32 to 69 years) and 150 age-matched controls (age range 25 to 62 years). The polymorphisms were identified by polymerase chain reaction/restriction fragment length polymorphism method and IL-1Ra polymorphism by variable number of identical tandem repeat analysis. Genotype distribution and allelic frequencies between patients and controls were compared., Results: A significant difference was found in the frequency distribution of the IL-1Ra gene polymorphism in patients with bladder cancer compared with the normal control group (P < 0.001), but no difference was found in the frequencies of the IL-1beta promoter region and exon 5 genotypes between patients with bladder cancer and controls (P = 0.112 and P = 0.953, respectively)., Conclusions: This is perhaps the first report on polymorphic changes in gene encoding IL-1Ra in patients with bladder cancer from India. Our data suggest that IL-1Ra intron 2 polymorphism seems to play a prominent role among the IL-1 gene cluster with respect to bladder cancer, and the association studies appear to be plausible in determining the cancer susceptibility and risk.

Introduction: Bladder cancer is a disease characterized by multiple recurrences. Some investigators assume urokinase to be involved in the causation of bladder cancer, although there is lack of genetic evidence. Our aim was to evaluate whether polymorphism of the urokinase gene is associated with transitional cell carcinoma (TCC) of the urinary bladder., Materials and Methods: The study included 100 patients (mean age 62.5 +/- 10.2 years) with TCC of urinary bladder and 150 healthy controls (mean age 60 +/- 11.5 years) living in the same area. Polymerase chain reaction (PCR)-based restriction analysis was used to identify the C/T polymorphism of the urokinase gene. Genotyping distribution and allelic frequencies between patients and controls were compared., Results and Conclusion: There was a significant difference in the frequency distribution of the urokinase gene 3'-UTR C/T polymorphism in bladder cancer patients as compared to the normal control group (p < 0.05), but no significant difference in allelic frequencies or in carriage rates between bladder cancer patients and normal controls were observed. Our study suggests that urokinase gene polymorphism may be associated with bladder cancer and can thus serve as a potential genetic marker in screening for the possible causes of bladder cancer. Perhaps analysis of patients with superficial bladder TCC and mutated urokinase might help clarify this aspect in large cohort studies in different populations.

Objective: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. We examined the association of the GST gene polymorphism with sporadic bladder cancer patients in Northern India., Material and Methods: The study constituted of 106 bladder cancer cases and 370 age-matched controls. The GSTT1 and GSTM1 null genotypes were identified by multiplex PCR and GSTP1313 A/G by Polymerase Chain Reaction/Restriction Fragment Length Polymorphism method (PCR/RFLP)., Results: We observed non-significant association in null alleles of the GSTM1 (p = 0.611, OR = 1.12, 95% CI = 0.72-1.74 and GSTT1 (p = 0.135, OR = 1.45, 95% CI = 0.89-2.37) with risk of bladder cancer. However, the G/G genotype of the GSTP1 gene polymorphism was highly significant when compared to controls (p=0.000, OR = 7.12, 95% CI = 3.14-16.16). The combined analysis of the three risk genotypes demonstrated further increase in the risk of bladder cancer (p = 0.000, OR = 7.29 95% CI = 2.81-18.93)., Conclusion: Our study demonstrated that GSTP1313 G/G polymorphism is a strong predisposing risk factor for bladder cancer. Combination of three GST genotypes association exhibiting gene-gene interaction further substantiates the increased risk of bladder cancer.

The present study was conducted (1) to examine whether the GSTT1- and GSTM1-null genotypes are risk factors for bladder cancer, and (2) to study possible association of tobacco usage and age strata with genotype of these patients. This case control study was undertaken over a period of 19 months and included 106 bladder cancer patients and 182 controls; both patients and controls originated from northern part of India. The GSTT1 and GSTM1 genotypes were identified by multiplex PCR in peripheral blood DNA samples. Genotype frequencies among patients and controls were assessed and the association of the genotypes with smoking habits and gender of the patients were statistically determined by the chi(2) test. Frequencies of null genotypes in GSTT1 and GSTM1, were 16% (29/182) and 30% (54/182), respectively, in control individuals. The frequencies of GSTT1- and GSTM1-null genotypes in bladder cancer patients were 26% (28/106) and 40% (42/106), respectively. In conclusion, our study demonstrated that the null genotypes of GSTT1 and GSTM1 were substantially at higher risk for bladder carcinoma compared to the normal healthy controls. The GSTT1- and GSTM1-null genotypes did not show significant association with tobacco usage in bladder cancer patients. However, the null genotypes were statistically significant in female relative to male bladder cancer patients.