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The bladder is a muscular, balloon like organ that collects the urine from each kidney to bladder through a narrow tube, ureter. The urine from bladder is eliminated through another narrow tube called urethra . Smoking highly increases the risk of bladder cancer, an estimated 57,400 cases were found in US and an estimated of 12,500 people died due to smoking induced bladder cancer [2, 3]. However, quitting helps in reducing the risk of developing cancer drastically 
Smoking is the major cause of bladder cancer in smoking population. The chance of getting bladder cancer in smokers is 2-3 times higher than those compared to non smokers . Tumor in the bladder develops due to its interactions with the carcinogenic substances like polyaromatic hydrocarbons (PAH) in the tobacco smoke rather than a direct exposure to them . PAH targets the bladder through blood . The carcinogens from the tobacco smoke are directed from lungs into the blood stream and reach all parts of the body. The blood is filtered by kidneys and concentrated into the urine. The urine is stored and discharged from the bladder, hence the carcinogens in the urine mount up and targets the linings of the bladder walls called the urothelial cells. This damage to the cell lining makes the smoker more likely to develop bladder cancer [4, 10]. In research study it was found that the risk of bladder cancer is not associated with tar or nicotine content in the cigarette but depends on how deeply the smoker inhales the smoke . The tumor can obstruct the flow of urine into the bladder or from the bladder, thus an incomplete bladder emptying feeling, a feeling of frequent urination which is painful . In spite of low concentrations of nicotine or tar, yet smokers developed cancer of bladder was of interest to the researchers. They suggested that it would be due to type of nicotine used (the intensity of carcinogenicity), as well as presence of additional amount of naphthylamine in the cigarette . Experiments reveal that aromatic amines play a major role in cancer induction .
TYPES OF BLADDER CANCER
Based on the appearance of the carcinoma, bladder cancer can be of the following types:
A common form of tumor cells that are formed on the bladder wall lining are called transitional cell carcinoma (TCC)
Few tumor cells grow differently than TCC although they come from the cell lining and are called the squamous cell carcinoma
The rarest form of cancer is called Adenocarcinoma arising from glandular cells in the bladder wall
EFFECT OF SMOKING ON BLADDER AT GENETIC LEVEL
Genetic differences among individuals make them susceptible or prone to developing cancer . Although, smoking is one of the major risk factor for causing bladder cancer (50%) in men  not all smokers developed bladder cancer .
NAT has two isozymes NAT1 and NAT2 located on chromosome 8 and has a 870-base pair long open reading frame. Both the isozymes are polymorphic in nature, NAT1*10 is a polymorphism on NAT1 and two mutants in NAT2 drastically reduces the enzyme activity. NAT are known to metabolize arylamines . Arylamines, the carcinogens in tobacco are detoxified by NAT2 enzymes while NAT1 activates these carcinogens to a highly reactive species that form arylamine-DNA adducts on bladder epithelium . NAT2 metabolizes arylamines in liver where they are N-acetylated to less reactive forms, inversely, O-acetylation in bladder epithelium by the gene NAT1 due to N-hydroxylation by CYPA1 genes makes them more reactive [16, 19]. An increased risk of bladder cancer was observed in smokers with NAT1*10 allele and NAT2 slow acetylators compared to smokers with fast acetylator NAT2 genotype and those without NAT1*10 gene . Polymorphisms in NAT are known to result in two phenotype variants expressing slow and fast acetylation. Strong association is established between NAT2 gene polymorphism and bladder cancer risks, with slow acetylators to have increased risk . Smokers who are slow acetylators showed high grade tumors (G3) or an advanced tumor stage (pT2-pT4). XPD genes play a major role in nucleotide excision repair (NER) mechanism to open the DNA helix and to repair the damaged DNA. XPD is associated with transcription-factor complex (TFIIH) which is involved in transcription, apoptosis and NER, thus helps to maintain the stability of TFIIH during transcription. Hence any alterations in XPD gene would affect the DNA repair mechanism and is hypothesized to cause smoking-induced bladder cancer. A study showed that polymorphism on the 751 codon of XPD causing Lys to Gly change would be a combined effect of the allelic variants of NAT1 and NAT2 genes on XPD .
Slow acetylation genotypes of NAT2 also has shown to have higher risks of developing bladder cancer compared to those who normal NAT2 genotypes . Individual susceptibility to bladder cancer has been hypothesized due to the presence of allelic variants on NAT2 gene. Thus NAT2 gene plays a major factor in determining the risk of having bladder cancer .
GLUTATHIONE S- TRANSFERASE 
Glutathione S transferase is involved in detoxification of the tobacco related carcinogenic compounds. The four sub genes of GST protein family are GSTP, GSTT, GSTM, and GSTA and are involved in inactivation of the carcinogens and protect the macromolecules from damage. GSTP1 has two alleles - GSTP1a with five fold greater enzymatic properties compared to the other allele GSTP1b which is suggested to efficiently modify benzopyrene diol epoxide (BPDE). The study investigated and concluded that individuals with Val 105 variant compared to Ile 105 were less susceptible to the risk of developing bladder cancer. Results indicated increased risk of bladder cancer due to variant Ile at 105. While less susceptibility was found on smokers with Val/Val than heterozygous Val/Ile or wild type gene. It was also found that a smoker with null genotype of GSTM1 is associated to have higher risks of developing bladder cancer  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459966/
NAD(P)H quinone oxidoreductase - NQO1
NAD(P)H quinone oxidoreductase is present on 16q22 and is thought to have dual function of activating and detoxifying the carcinogens in tobacco smoke. The formation of benzo[a]pyrene quinione- DNA adducts is prevented by this gene while in unison it activates the carcinogenic heterocyclic amines . Polymorphism in this gene would affect its activity, thus resulting in DNA adducts and increasing the chances of cancer. A transition from C to T at base pair 609, codon 187 is associated with decreased activity of the gene . The presence of raised levels of 4-aminobiphenyl, the known carcinogen  adducts to DNA and is seen in the blood is incredible indicator of disclosure to carcinogens. Such increased levels are observed in smokers with bladder cancer [16, 17]. 4-aminobiphenyl when activated via N-hydroxylation by cytochrome P450 genes forms adducts with the blood and circulates freely in a reactive form and gets transported to bladder where it can bind with DNA and induce cancer. The epithelium linings of the bladder of smokers are the evidence for 4-aminobiphenyl adducts to hemoglobin. These adducts are lower in smokers who were rapid acetylators as N-acetylation could deactivate the carcinogen while they were abundant in smokers who were slow acetylators . Hence high levels of adducts in the blood is directly proportional to tremendous risk of bladder cancer .
X-RAY REPAIR CROSS COMPLEMETING GROUP 1 and 3
XRCC1 is involved in single stranded DNA damage repair via base excision repair mechanism while XRCC3 is a DNA double stranded break-repair gene via homologous or non-homologous end-joining pathways . XRCC1 genes with a variance at 26651 were not of much importance as no functional changes were observed due to the maintenance of proline amino acid inspite of substitution of adenine (A) by guanine (G). XRCC1 -26304 C>T, XRCC1 - 28152A>G, XRCC1 -28752A are various SNPs observed to have induced bladder cancer, individually at a very low rate; however, a combination of these SNPs increases the risk immensely . Haplotypes of XRCC1 - CGA and CGG significantly elevate cancer risks . XRCC1 with Arg280His variant is ineffectively localized on a defective DNA leading to faulty base excision repair mechanism . A three-fold increase in bladder cancer has been associated with bladder cancer with Arg280His variant allele, although present only in low frequency, studies report the carriers of this allele are strong candidates of bladder cancer . A strong association has been reported between XRCC3 polymorphism in XRCC3 at 18067C>T (Thr241Met) and smoking induced bladder cancer progression [23, 16]. Individuals with two copies of the mutated allele (TT/TM versus MM) have elevated risks of bladder cancer . TAT haplotype of XRCC3 gene also account to extend the possibility of cancer . The gene-gene interaction of XRCC3 and NAT-2, slow acetylator genotype is suggested to have noteworthy role in cancer progression . Smokers with low DNA repair capacity (DRC) are associated with 3.42 fold increased risk of getting bladder cancer . XRCC3 M241T might act as an effect modifier of smoking .
ERCC2 is observed to function as an ATP-dependent DNA helicase in Nucleotide Excision Repair pathway (NER). Two significant polymorphisms in ERCC2 gene reported were D312N (rs1799793) and K751Q (rs13181), while statistically they were not considerable due to lack of large population study. However, strong association has been established between bladder cancer risk and ERCC2 D312N . However, D312N allelic polymorphism has been observed to have 2.5-fold increase in UV-induced apoptosis in lymphoblastoid cell line compared to K451Q allele .
DNA REPAIR GENES
Cigarette has colossal amount of carcinogens that forms bulky DNA adducts, base damage and DNA double strand breaks in urothelial cells. DNA repair genes meant to resolve the damages. The metabolism of carcinogenic compounds results in free radicals that are detrimental. The DNA repair genes like XPC and ERCC2 are involved in repairing the bulky adducts while NBN and XPC play major role in preventing the genes from oxidative damage .
The research studies at International Consortium of Bladder Cancer reveals strong association of polymorphism among DNA repair genes . These genes involve ERCC2 with D312N (rs1799793) and K751Q (rs13181) polymorphisms, NBN with E185Q (rs1805794), XPC with A499V polymorphism (rs2228000). Among the two polymorphisms in ERCC2, 312N shows the strongest association with elevated risk of bladder cancer among smokers. This association was although significantly plausible . NBN is a member of MRN (MRE11-RAD50-NBS1) complex involved in detection of DNA strand breaks. The polymorphism of NBN E185Q is a strong association between the oxidative stresses due to cigarette smoking . A noteworthy role has been established between smoking and bladder cancer risk for carriers of NBN codon with 185Q allele . Thus smokers with QQ genotype shall be more susceptible to cancer development compared to EE genotype. XPC gene plays a key role in oxidative damage removal along with global NER mechanism . Although there is evidence for XPC gene related to bladder cancer risks, the functional consequences of the polymorphism genes are not worth mentioning .
Bladder cancer associated with smoking has TP53 as a target influencing the pattern of TP53 mutation due to carcinogenic factors in cigarette . In one of the studies it was stated that transition from A: T -G: C at the CPG plot is common in smokers than non-smokers . A codon 270 might be considered as the mutational hot spot for bladder cancer induced by smoking. A region from 280 to 285 is meant to be mutational hot spot for TP53 gene related to bladder cancer .
Caspase is a family of proteins that act as an initiator for the apoptosis cascade. CASP8, gene that encodes for the protein Caspase-8 is located on the 2q33. Studies have been found out that CASP8, a regulator of apoptosis with a promoter variant -652 6N ins/del is protective against many cancers in lungs, breast, esophageal, stomach, colorectal and cervical. However, an association has been established with this variant and bladder cancer especially among smokers.
A significant association could not be established between CCND1 genotype and bladder cancer due to variations in results prepared by the researches. One of the findings reported the presence of AA genotype responsible for bladder cancer while two other findings reported no such association . Wang et al showed the presence of high grade tumor in smokers with CCND1 A allele genotype
Variation in p21 gene on codon 31, in a single study exposed the connection with bladder cancer .A decreased risk of bladder cancer is found on exon 4 of DRD4 with G/G genotype . Lower risks were also observed for MMP-2 genes over-expression. The role of immunomodulatory genes also is noteworthy. IL6 variant is one among to be associated with towering risk of bladder cancer . Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. The activity of MTHFR is reduced due to a missense mutation of a C to T transition forms valine instead of alanine . Remarkable involvement of TNF polymorphism TNF +448A and TNF -859T and the grade of bladder cancer is reported . POLB has strong linkage with bladder cancer and loss of POLB locus due to smoking is evident for its role in bladder cancer . FGFR is often found in the urothelial cell linings of bladder illustrating it to be an important target site for bladder cancer. The association of FGFR with TP53 has been studied; however, the mutations in TP53 but not in FGFR were affected in recent smokers . The mutations were observed on the splice receptor site of intron-6 and also on exons from 4 to 9 . An association has been recognized between bladder cancer and P2RY5 gene present within intron 17 of RB1, a tumor suppressor gene. The functions of RB1 have been found to have lost following the loss of functions of the forerunner (FR) genes present in the immediate vicinity of RB1 gene .
CHROMOSOME 9 and bladder cancer
Smoking induced bladder cancer has been linked to chromosome 9 in major research studies.
DECREASED RISK OF BLADDER CANCER
A decreased risk of bladder cancer has been recognized for genes with various polymorphisms: ERCC1 with polymorphism at 19007 due to deletion of the cytosine (C) residue, XRCC3 -4541T>C among never smokers, XRCC3 -17893A>G has shown reduced risks to bladder cancer . A low frequency of variant allele of PCNA gene has been reported due to deletion of C allele at 6084 . Wu et al in his research narrowed down his findings from 85 genes to a single gene with increased risk of cancer in carriers of 312Asn allele of ERCC2 gene . A variant of XRCC3 Thr241Met is predicted to have protective function against bladder cancer confined to only heavy smokers . A polymorphism in minor allele rs 717754 of SLC6A4 has been observed to influence three-fold increased risk in mounting bladder cancer .
Biological therapy, that is, using the body's immune system against the disease can prevent the cancer cells from coming back
Ex-smokers decreased their risk of developing bladder cancer by 30% on those who left smoking in a period of 1-4 years and about 60% after 25 years of smoking cessation, although the risk was not equal to the level as compared to the non-smokers .