Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression

Abstract

Urothelial cancer has served as one of the most important sources of information about the mutational events that underlie the development of human solid maligancies. Although "field effects" that affect the entire bladder mucosa appear to initiate disease, tumors develop along two distinct biological "tracks" that present vastly different challenges for clinical management. Recent whole genome methodologies have facilitated even more rapid progress in the identification of the molecular mechanisms involved in bladder cancer initiation and progression. Specifically, whole organ mapping combined with high resolution, high throughput SNP analyses have identified a novel class of candidate tumor suppressors ("forerunner genes") that localize near more familiar tumor suppressors but are disrupted at an earlier stage of cancer development. Furthermore, whole genome comparative genomic hybridization (CGH) and mRNA expression profiling have demonstrated that the two major subtypes of urothelial cancer (papillary/superficial and non-papillary/muscle-invasive) are truly distinct molecular entities, and in recent work our group has discovered that muscle-invasive tumors express molecular markers characteristic of a developmental process known as "epithelialto-mesenchymal transition" (EMT). Emerging evidence indicates that urothelial cancers contain subpopulations of tumor-initiating cells ("cancer stem cells") but the phenotypes of these cells in different tumors are heterogeneous, raising questions about whether or not the two major subtypes of cancer share a common precursor. This review will provide an overview of these new insights and discuss priorities for future investigation.

Loss of Imprinting as an Epigenetic Marker in Bladder Cancer

“…In less than one third of the cases, the tumor is invasive and compromises the muscle layer. Despite this low risk of metastasis, bladder cancer has a high risk of recurrence [126]. The IGF2 gene was shown to have a role in invasion and metastasis in several types of cancer (reviewed in [127].…”

Bladder Cancer and Schistosomiasis: Is There a Difference for the Association?

“…Among the most common genetic changes in bladder cancer is the loss of heterozygosity (LOH) on chromosomes 9p and 9q, which is found regardless of tumor grade and stage (Jacobs et al,2010& McConkey et al, 2010. A prospective study stated that there was no evident line of demarcation between schistosomiasis-associated and non schistosomiasisassociated bladder cancer in terms of LOH of microsatellite markers on chromosome 9.…”

miR-143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling

“…Approximately 90% of bladder cancer cases are urothelial carcinomas, previously named transitional cell carcinomas. The majority of bladder cancers are low-grade, non-muscle-invasive cancers, which account for up to 70-80% of cases, and which seldom progress to the muscle-invasive stage (3,4). However, 10-20% of patients are diagnosed with high-grade and muscle-invasive tumors, exhibiting aggressive clinical behavior (3).…”