Molecular Evidence Supporting Field Effect in Urothelial Carcinogenesis

Abstract

Purpose: Human urothelial carcinoma is thought to arise from a field change that affects the entire urothelium. Multifocality of urothelial carcinoma is a common finding at endoscopy and surgery. Whether these coexisting tumors arise independently or are derived from the same tumor clone is uncertain. Molecular analysis of microsatellite alterations and X-chromosome inactivation status in the cells from each coexisting tumor may further our understanding of urothelial carcinogenesis. Experimental Design: We examined 58 tumors from 21patients who underwent surgical excision for urothelial carcinoma. All patients had multiple separate foci of urothelial carcinoma (two to four) within the urinary tract. Genomic DNA samples were prepared from formalin-fixed, paraffinembedded tissue sections using laser-capture microdissection. Loss of heterozygosity (LOH) assays for three microsatellite polymorphic markers on chromosome 9p21 (IFNA and D9S171), regions of putative tumor suppressor gene p16, and on chromosome17p13 (TP53), the p53 tumor suppressor gene locus, were done. X-chromosome inactivation analysis was done on the urothelial tumors from 11female patients. Results: Seventeen of 21 (81%) cases showed allelic loss in one or more of the urothelial tumors in at least one of the three polymorphic markers analyzed. Concordant allelic loss patterns between each coexisting urothelial tumor were seen in only 3 of 21 (14%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the multiple coexisting urothelial tumors was seen in only 3 of 11 female patients; of these 3 cases, only one displayed an identical allelic loss pattern in all of the tumors on LOH analysis. Conclusion: LOH and X-chromosome inactivation assays show that the coexisting tumors in many cases of multifocal urothelial carcinoma have a unique clonal origin and arise from independently transformed progenitor urothelial cells, supporting the ''field effect'' theory for urothelial carcinogenesis.

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

“…That may highlight the existence of different histopathologies in the same specimen. A recent study suggests that both field cancerization and monoclonal tumor spread may coexist in the same patient (Jones et al, 2005). In this study, molecular evidence supported an oligoclonal origin for multifocal Urothelial carcinoma.…”

Staging and reporting of urothelial carcinoma of the urinary bladder

“…There is evidence that multifocal urothelial carcinoma can arise through independent concurrent genetic events at multiple locations in the lower urinary tract. 138,139 Other studies, however, have suggested a monoclonal origin for multifocal urothelial carcinoma. 140,141 In cases with multifocal cancer, the location and size of each tumor should be documented in the gross description.…”

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

“…Molecular genetic studies support the monoclonality theory and indicate that tumour cells spread to multiple sites by intraepithelial or intraluminal seeding (Sidransky et al, 1992;Habuchi et al, 1993;Takahashi et al, 1998;Dalbagni et al, 2001), while other studies have shown that field effect underlies some multifocal urothelial tumours (Paiss et al, 2002;Jones et al, 2005). An understanding of the mechanism leading to accumulation of genetic alterations during multifocal tumour development may provide new prospects for both the early detection and prevention of the recurrence of urothelial cancer.…”