| JWA (GenBank: AF070523, 1998), also known as ARL6IP5, a novelall-trans retinoic acid (ATRA) responsible gene associated with cellulardifferentiation, was initially isolated from ATRA-treated primary humantracheal bronchial epithelial ceils by Zhou et al, which was mapped onchromosome 3p14, consisting of 3 exons and 2 introns. The full length ofcDNA sequence of the gene contains 2114 nucleotides, which encoding188 amino acids. Within the identified 3000 base pairs of promotersequence of the gene, several cis- response elements, such as phorbolester response element (TRE), stress response element (SRE), and the retinoic acid response element (RARE) were identified. Our previousinvestigations have demonstrated that the JWA gene was not onlyimportant for chemical (e.g. TPA (12-O-tetradecanoylphorbol-13-acetate), ATRA, 4HPR (N-(4-hydroxyphenyl) retinamide), hemin, andAs2O3) mediated directional cell differentiation and apoptosis in primarycultured APL cells and leukemia cell lines (e.g. NB4, HL-60, K562 andU937), but also was actively responsive to environmental stressstimulations (e.g. heat shock, oxidative stress). JWA is positivelyinvolved in the DNA damage and repair processes induced by H2O2 andB(a)P- induced oxidative stress, suggesting that JWA may be responsiveto reactive oxygen species (ROS) and involved in signaling of DNAdamage and repair processes.It has been well established that ROS induced DNA damage, animportant risk factor for various diseases including cancers. Geneticdamages resulting in positive proliferative signals, loss of tumorsuppressor gene function, inhibition of developmental programs,blockade of cell death pathways, resistance to genotoxic agents andavoidance of host defense mechanisms were documented to play a part inthe pathogenesis of some types of leukemia. Studies demonstrated thattobacco smoking, emission of industrially related aromatic amines andamides, alcohol and some anticancer drugs are risk factors of thedevelopment of bladder cancer, which may lead to carcinogenesis by inducing DNA damage. Furthermore, the JWA gene is located atchromosome 3p, the region was reported to associate with variouscancers including lung and renal cancer.There is accumulating evidence to support an association betweenSNP in genes involved in biological processes (such as DNA repair, cellcycle, and apoptosis) and cancer. As useful genetic biomarkers, someSNPs were identified to be associated with altered susceptibility todiseases, including cancer. Most SNPs are usually located near a genefound to be associated with a certain disease. Occasionally, a SNP may beassociated with the development of a disease. Therefore, SNP can be usedto search for and isolate the disease-causing gene.Our latest investigation has demonstrated that two novelpolymorphisms in the JWA gene (-76G＞C and 723T＞G) were associatedwith the risk of bladder cancer, leukemia and digestive system cancers.The-76G＞C could increase the risks of the above-mentioned cancers. The-76C allele might decrease or prevent the role of the JWA promoter inregulating the transcription of the JWA gene, resulting in down regulationor deletion of the JWA gene expression, particularly in the presence ofoxidative stress. Therefore, JWA may play a role in DNAdamage-associated development of cancers and that its variants maycontribute to individual variation in susceptibility to environmentallyinduced cancer. The aim of this project is designed to investigate the associationbetween JWA gene polymorphisms and the risk of leukemia and bladdercancer in Chinese Han population, by JWA gene polymorphisms analysiscombined with -76G＞C identified from the same bladder cancer sample,using PCR-SSCP and PCR-RFLP for 202 cases of various kinds ofleukemia and 215 cases of bladder cancer in case-control studies. Incombination with the exposure of smoking and alcohol, we try to evaluatethe interaction of the gene-environment during the development ofbladder cancer, and to search for the useful genetic biomarker associatedwith altered susceptibility to leukemia and bladder cancer.Part one: The association between JWA gene polymorphisms and therisk of leukemogenesis in a Chinese population.Epidemiologic and genotypic data have shown that many leukemiacells have more than one recurring mutations, either as point mutations,gene rearrangements and/or chromosomal translocations. As a novel celldifferentiation-associated gene, JWA was associated with severalchemicals induced directional differentiations in primary and humanmyeloid leukemia cell lines. Here, we designed a hospital-basedcase-control study between JWA SNPs of 380G＞C and 454C＞A(NM006407.2) in JWA exon 2 variants and risk of leukemia in 202leukemia patients and 289 cancer-free controls. The variants weredetermined by polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP), followed by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). We found thatthe 454A allele was associated with significantly increased risk of multikinds of leukemia. When the 454CC genotype was used as the reference,the 454CA, AA and CA+AA genotypes were associated with asignificantly increased risk of leukemia (adjusted odd ratio (OR)=3.59,6.50, 4.13; 95％confidence interval (CI)=2.29～5.63, 3.60～11.76,2.68～6.37, respectively. Its function remains to be further investigated.Part two: The association between JWA gene polymorphisms and therisk of bladder cancer in a Chinese population.Studies demonstrated that ROS induced DNA damage play animportant role in carcinogenesis, including the development of bladdercancer, to which tobacco smoking and alcohol are risk factors. As anenvironmental responsive gene, JWA may be involved in signaling ofDNA damage and repair processes induced by ROS. Here, we alsodesigned a hospital-based case-control study between JWA SNPs in JWAexon 2 variants and risk of bladder cancer in 215 bladder cancer patientsand 250 cancer-free controls with the same methods. We identified twonovel SNPs, 380G＞C and 454C＞A (NM006407.2) from the cases andcontrols. Ditto, the 454A allele was associated with significantlyincreased risk of bladder cancer. Logistic regression analysis revealed asignificantly increased risk of bladder cancer was associated with the 454CA and 454AA genotypes (adjusted OR=1.63, 95％CI=1.09～2.44for 454CA and 2.33, 1.26～4.31 for 454AA) compared with the 454CCgenotype. Linkage disequilibrium analysis indicated that the -76G＞C and454C＞A polymorphisms were in linkage disequilibrium (D'=0.383, P=0.006), suggesting that there existed haplotypes that may exert anenhanced effect on the risk. When the GC/GC genotypes with no variantallele were used as the reference, increased risk of bladder cancer wasassociated with the GC/CA (adjusted OR=4.05; 95％CI=1.89-8.67)and GA/GA (adjusted OR=2.29; 95％CI=1.14-4.52). When thehaplotype genotypes were regrouped by the number of variant alleles andthe GC/GC genotype 0 variant allele was used as the reference, the riskwas significantly increased as the number of variant alleles rose (P＜0.001). The association between the JWA -76G＞C and 454C＞A combinedvariant genotypes and risk of bladder cancer was further stratified bypotential confounding variables, such as age, gender, smoking anddrinking statuses. Individuals with 1-3 variant alleles associated withsignificantly increased risk of bladder cancer when compared with thosewith non- variant allele. The increased risk appeared to be morepronounced among older (＞65 years) individuals (adjusted OR=1.80;95％CI=1.07-3.03), male (adjusted OR=1.69; 95％CI=1.11～2.58),smokers (adjusted OR=1.94; 95％CI=1.11～3.37), and drinkers(adjusted OR=2.06; 95％CI=1.16～3.64). In conclusion, the potential functional genetic polymorphism454C＞A of the JWA gene appears to contribute to the increased risks ofmulti kinds of leukemia and bladder cancer in Chinese Han population,and it exerts an enhanced effect on the risk combined with -76G＞Cvariant genotypes. JWA genetic polymorphisms may be an effectivegenetic biomarker involving in the pathogenesis of bladder cancer,although its function remains further research. Larger studies includedifferent ethnics with more detailed environmental exposure status andmore detail clinical information of cases is need to be further investigated...
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