Patients with cancer of the urinary bladder often present with multiple tumors appearing at different times and at different sites in the bladder. This observation had been attributed to a 'field defect' in the bladder that allowed the ... Patients with cancer of the urinary bladder often present with multiple tumors appearing at different times and at different sites in the bladder. This observation had been attributed to a 'field defect' in the bladder that allowed the independent transformation of epithelial cells at a number of sites. Sidransky et al. (1992) tested this hypothesis with molecular genetic techniques and concluded that in fact multiple bladder tumors are of clonal origin. A number of bladder tumors can arise from the uncontrolled spread of a single transformed cell. These tumors can then grow independently with variable subsequent genetic alterations. Dyrskjot et al. (2003) reported the identification of clinically relevant subclasses of bladder carcinoma using expression microarray analysis of 40 well-characterized bladder tumors. Gene expression profiles characterizing each stage and subtype identified their biologic properties, producing potential targets for therapy.
Analysis of LOH at 11p13, a region containing the Wilms tumor suppressor gene (WT1; 607102), showed deletion at the CAT locus (115500) in 13 of 18 bladder cancers (72%), at the WT1 locus in 7 of 14 (50%), ... Analysis of LOH at 11p13, a region containing the Wilms tumor suppressor gene (WT1; 607102), showed deletion at the CAT locus (115500) in 13 of 18 bladder cancers (72%), at the WT1 locus in 7 of 14 (50%), and at the FSHB locus (136530) in 6 of 16 (38%). See 190020.0001 for a somatic mutation identified in the HRAS oncogene in a bladder carcinoma. See 190070.0002 for a somatic mutation identified in the KRAS oncogene in a bladder carcinoma. See 614041.0009 for a somatic mutation identified in the RB1 gene in a bladder carcinoma. Risch et al. (1995) demonstrated that the slow N-acetylation genotype (NAT2; 612182) is a susceptibility factor in occupational and smoking-related bladder cancer. Employing PCR-based genotyping, they investigated NAT2 type among 189 Caucasian bladder cancer patients attending a clinic in Birmingham, U.K. The results were compared to those from an age-matched nonmalignant Caucasian control population from the same region. Risch et al. (1995) found a significant excess of genotypic slow acetylators in patients exposed to arylamines as a result of their occupation or cigarette use. A higher proportion of slow acetylators was also found in most bladder cancer patients without identified exposure to arylamines when compared to the nonmalignant controls. Hruban et al. (1994) did a retrospective molecular genetic analysis of the bladder carcinoma that was the cause of death in the case of Hubert H. Humphrey (1911-1978), U.S. senator and vice president. In 1967, hematuria led to a diagnosis of chronic proliferative cystitis. Although urine cytology at that time was thought by one prominent cytopathologist to be diagnostic of carcinoma, a diagnosis of infiltrating carcinoma of the bladder was not made until August 1976. Hruban et al. (1994) analyzed both the invasive bladder carcinoma resected in 1976 and the filters prepared from urine in 1967. Both showed a transversion from adenine to thymine in codon 227, creating a cryptic splice site in exon 7 of the p53 gene (191170). The mutation resulted in the loss of several amino acids and in the production of a shortened, mutant p53 protein. This mutation was not present in nonneoplastic tissue of the resected bladder. Cappellen et al. (1999) found expression of a constitutively activated FGFR3 in a large proportion of 2 common epithelial cancers, bladder cancer and cervical cancer (603956). The most frequent FGFR3 somatic mutation in epithelial tumors was ser249 to cys (134934.0013), affecting 5 of 9 bladder cancers and 3 of 3 cervical cancers. In studies for bladder cancer predisposition, Wu et al. (2006) applied a multigenic approach using a comprehensive panel of 44 selected polymorphisms in 2 pathways, DNA repair and cell cycle control, and, to evaluate higher order gene-gene interactions, classification and regression tree (CART) analysis. This hospital-based case-control study involved 696 white patients newly diagnosed with bladder cancer and 629 unaffected white controls. Individually, only the asp312-to-asn polymorphism of the XPD gene (126340), the lys820-to-arg polymorphism of the RAG1 gene (179615), and an intronic SNP of the p53 gene (191170) exhibited statistically significant main effects. However, Wu et al. (2006) found a significant gene dosage effect for increasing numbers of potential high risk alleles in DNA repair and cell cycle pathways separately and combined. In addition, they found that smoking had a significant multiplicative interaction with SNPs in the combined DNA repair and cell cycle control pathways (P less than 0.01). All genetic effects were evident only in 'ever smokers' (persons who had smoked more than 100 cigarettes) and not in 'never smokers.' Moreover, subgroups identified with higher cancer risk also exhibited higher levels of induced genetic damage than did subgroups with lower risk. There was a significant trend of higher numbers of bleomycin- and benzo[a]pyrine diol-epoxide (BPDE)-induced chromatid breaks (by mutagen sensitivity assay) and DNA damage (by comet assay) for individuals in higher risk subgroups among cases of bladder cancer in smokers. Thus, higher order gene-gene and gene-smoking interactions included SNPs that modulated repair and resulted in diminished DNA repair capacity. This study confirmed the importance of taking a multigene pathway-based approach to risk assessment. Fliss et al. (2000) identified a somatic 21-bp deletion in the mitochondrial MTCYB gene in tumor tissue from a patient with bladder cancer. Dasgupta et al. (2008) found that overexpression of the deletion identified by Fliss et al. (2000) in murine bladder cancer cells resulted in increased tumor growth and an invasive phenotype in vitro and after injection into mice. Increased tumor growth was associated with shifts toward glycolysis and production of reactive oxygen species (ROS). Rapid cell cycle progression was associated with upregulation of the NFKB (164011) signaling pathway, and inhibition of ROS or NFKB diminished tumor growth in vitro. Transfection of the 21-bp deletion into human uroepithelial cells resulted in similar effects. The findings suggested that mitochondrial mutations may contribute to tumor growth. Van der Post et al. (2010) used a questionnaire-based survey to ascertain the risk of urogenital cancer in 95 families with HNPCC (see, e.g., 120435). Bladder cancer was diagnosed in 21 patients (90% men) from 19 families; 15 had mutations in the MSH2 gene (609309). Men carrying an MSH2 mutation and their first degree relatives had a cumulative risk by age 70 of 12.3% for bladder cancer and 5.9% for upper urinary tract cancer. Van der Post et al. (2010) concluded that patients with Lynch syndrome, particularly those carrying MSH2 mutations, have an increased risk of urinary tract cancer, which may warrant surveillance. Gui et al. (2011) sequenced the exomes of 9 individuals with TCC and screened all somatically mutated genes in a covalent set of 88 additional individuals with TCC with different tumor stages and grades. Gui et al. (2011) discovered a variety of genes previously unknown to be mutated in TCC. Notably, they identified genetic aberrations of the chromatin remodeling genes UTX (300128), MLL (159555), MLL3 (606833), CREBBP (600140), EP300 (602700), NCOR1 (600849), ARID1A (603024), and CHD6 in 59% of 97 subjects with TCC. Of these genes, UTX was altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Solomon et al. (2013) reported the discovery of truncating mutations of STAG2 (300826), which regulates sister chromatid cohesion and segregation, in 36% of papillary noninvasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Solomon et al. (2013) stated that their studies suggested that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. Guo et al. (2013) reported genomic analysis of transitional cell carcinoma (TCC) by both whole-genome and whole-exome sequencing in 99 individuals. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, Guo et al. (2013) identified additional altered genes and pathways that were implicated in TCC. Guo et al. (2013) discovered frequent alterations in STAG2 (300826) and ESPL1 (604143), both involved in the sister chromatid cohesion and segregation process. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the sister chromatid cohesion and segregation process. Balbas-Martinez et al. (2013) found that STAG2 was significantly and commonly mutated or lost in urothelial bladder cancer, mainly in tumors of low stage or grade, and that its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in nonexpressing cells led to reduced colony formation. Balbas-Martinez et al. (2013) found that STAG2 is a novel urothelial bladder cancer tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.