Urology>>>>>Bladder Cancer
Question 4#

Regarding the molecular biology of bladder cancer pathogenesis, the following are true, EXCEPT:

A. Chromosome 10 loss of heterozygosity (LOH) is found in more than 50% of all bladder tumours
B. Low-grade pTa tumours usually have alterations in the RAS-MAP kinase signal transduction pathway, the most frequent being fibroblast growth factor receptor 3 (FGFR3) mutations on chromosome 4p
C. Over-expression of the genes that encode receptor tyrosine kinases such as EGFR (epidermal growth factor receptor) and the Erb2 receptor have been reported
D. Muscle-invasive tumours and CIS frequently have alterations in the p53 and retinoblastoma (pRb) pathways that control the cell cycle

Correct Answer is A

Comment:

Answer A

Multiple genetic and epigenetic alterations have been described in bladder cancer, including those that affect signal transduction, the cell cycle, invasion, angiogenesis and apoptosis. Most genetic events to date have been identified in high-grade and muscle-invasive bladder cancer. Many of these events are also found in CIS, confirming the likely progression to muscle-invasive TCC via CIS.

Chromosome 9 loss of heterozygosity (LOH) is found in found in more than 50% of all bladder tumours regardless of stage and grade. Current evidence suggests that genetic alterations on chromosome 9q are an early event in bladder tumour formation. Other chromosomal alterations are loss of 17p, 3p, 13q, 18q and 10q. These are noted more frequently in high than in low grade and stage disease.

The key tumour suppressor genes altered in bladder cancer are TP53 and RB1, pathways that control the cell cycle. (P53 is a classic tumour suppressor gene and in its mutated form it is overtly stabilised and hence it is overexpressed in invasive TCC). TP53 gene is the most commonly mutated gene in high-grade muscle-invasive urothelial cancer. The TP53, retinoblastoma (RB), PTEN genes and loss of chromosome 17 are all associated with high-grade cancer. Alterations in TP53, RB and PTEN are poor prognostic indicators.

Several known oncogenes are altered in TCC. Activating point mutations of FGFR3 have been identified in approximately 40% of bladder tumours overall. Mutant FGFR3 is predicted to activate the RAS-MAP kinase pathway

Further Reading:

1. Bryan RT, Billingham LJ, Wallace DM. Molecular pathways in bladder cancer part 1&2. BJU Int 2005; 95(4): 485–496.
2. Knowles MA. Novel therapeutic targets in bladder cancer: Mutations and expression of FGF receptors. Future Oncol 2008; 4: 71–83.