Molecular evidence supporting field effect in urothelial carcinogenesis.
OBJECTIVE
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.


METHODS
We examined 58 tumors from 21 patients 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, paraffin-embedded 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 chromosome 17p13 (TP53), the p53 tumor suppressor gene locus, were done. X-chromosome inactivation analysis was done on the urothelial tumors from 11 female 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.


CONCLUSIONS
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.
Jones
Timothy D
TD
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Wang
Mingsheng
M
Eble
John N
JN
MacLennan
Gregory T
GT
Lopez-Beltran
Antonio
A
Zhang
Shaobo
S
Cocco
Amy
A
Cheng
Liang
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics; D016899:Interferon-beta / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008954:Models, Biological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000378:metabolism / Q000473:pathology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016898:Interferon-alpha; D016159:Tumor Suppressor Protein p53; D016899:Interferon-beta