Bladder cancer - molecular biology and genetics

In addition to marked racial differences, it has been observed that there is wide variation in bladder cancer risks amongst populations with similar exposure to tobacco andoccupational bladder carcinogens. 1

Genetically determined differences in metabolic activation and detoxification of bladder carcinogens may play an important role in individual variations in susceptibility to the disease. Associations of bladder cancer with genetic variants ( Polymorphisms) of, for example, the enzymes glutathione S-transferase (GST) and N-acetyl transferase (NAT) have been proposed.

GST is the product of the GSTM1 gene and is involved in the detoxification of polycyclic aromatic hydrocarbons found in tobacco smoke. Around 50 per cent of Caucasians and Asians have a deleted GSTM1 gene and there is evidence that this genetic status is associated with a modest increase in the overall risk of bladder cancer. 2 Furthermore, there appears to be a GSTM1 gene dosage effect, with individuals with either no copies, as well as those with a single copy of GSTM1, having increased bladder cancer risk compared to those with two copies of the gene. 3

The N-acetyl transferase 2 (NAT2) enzyme is important in the inactivation of aromatic amines and is present in ‘fast’ and ‘slow’ forms, indicating the speed at which it is able to inactivate environmental carcinogens. Studies have suggested that people who carry the ‘slow’ variant are at increased risk of bladder cancer and that this may be especially true for smokers. 3

Recent studies identify polymorphisms in DNA repair genes as possible risk factors. Two relatively large recent series support the view that genetic variation in the nucleotide excision repair pathway influences bladder cancer risk. 4,5 Further research into the genetic understanding of individual susceptibility to bladder cancer, the interaction of environment and genes in disease pathogenesis and the opportunities for prevention is needed.

There have been few reported cases of inherited bladder cancer and familial cases are usually part of the HNPCC syndrome. 6,7 One study has shown a particularly high risk for brothers of bladder cancer probands diagnosed before the age of 45 years which may reflect an X linked susceptibility gene. 8 However, a recent study which used a relatively powerful technique failed to identify any genetic abnormalities in hereditary bladder cancer patients. 9

A number of genetic changes have been identified in bladder tumours. 10-12 Numerous alterations have been reported in invasive cancers but fewer in non-invasive forms. Both tumour types commonly exhibit deletions affecting chromosome 9 (50-60% of cases) and a number of candidate genes have been identified including CDKN2A (INK4a). The fibroblast growth factor 3 gene (FGFR3) is mutated in more than 70% of non-invasive cancers. Other reported alterations include mutations affecting the cyclin D1 gene (CCDN1), oncogenes including ERBB2 and  tumour suppressor genes including TP53. 10-12

Research into the gene alterations that drive the development of bladder cancer, and more detailed understanding of the molecular pathways involved in disease progression continues. The increasing use of microarray technology to study gene expression will offer improved prospects for identifying prognostic and predictive factors and continue to the development of new targeted therapies.

The search continues for a better and less invasive diagnostic test for bladder cancer. Raised levels of the DNA replication initiation factor Mcm5 in urine have been shown to provide a highly sensitive and specific marker for primary and recurrent bladder cancers. Clinical trials are currently ongoing. . 13 A recent study showed that testing for nuclear matrix proteins (NMP22) in urine samples alongside cystoscopy could detect 99% of recurrent bladder cancers. . 14

Studies of genetic variation in individual susceptibility to bladder carcinogens will lead to a better understanding of the disease and provide new leads for prevention. But prevention, through minimising exposure to known carcinogens, particularly those in tobacco smoke, will remain a priority.