Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia.

TitleEvidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia.
Publication TypeJournal Article
Year of Publication2006
AuthorsKim, M-S, Jeong, J, Majewski, T, Kram, A, Yoon, D-S, Zhang, R-D, Li, J-Z, Ptaszynski, K, Kuang, TC, Zhou, J-H, Sathyanarayana, UG, Tuziak, T, Johnston, DA, Grossman, HB, Gazdar, AF, Scherer, SE, Benedict, WF, Czerniak, B
JournalLab Invest
Volume86
Issue2
Pagination175-90
Date Published2006 Feb
ISSN0023-6837
KeywordsAged, Aged, 80 and over, Alleles, Chromosome Mapping, Chromosomes, Human, Pair 13, DNA Methylation, Humans, Immunohistochemistry, Middle Aged, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Recombination, Genetic, Retinoblastoma Protein, Urinary Bladder Neoplasms
Abstract

In this paper, we present whole-organ histologic and genetic mapping studies using hypervariable DNA markers on chromosome 13 and then integrate the recombination- and single-nucleotide polymorphic sites (SNPs)-based deletion maps with the annotated genome sequence. Using bladders resected from patients with invasive urothelial carcinoma, we studied allelic patterns of 40 microsatellite markers mapping to all regions of chromosome 13 and 79 SNPs located within the 13q14 region containing the RB1 gene. A whole-organ histologic and genetic mapping strategy was used to identify the evolution of allelic losses on chromosome 13 during the progression of bladder neoplasia. Markers mapping to chromosomal regions involved in clonal expansion of preneoplastic intraurothelial lesions were subsequently tested in 25 tumors and 21 voided urine samples of patients with bladder cancer. Four clusters of allelic losses mapping to distinct regions of chromosome 13 were identified. Markers mapping to the 13q14 region that is flanked by D13S263 and D13S276, which contains the RB1 gene, showed allelic losses associated with early clonal expansion of intraurothelial neoplasia. Such losses could be identified in approximately 32% bladder tumor tissue samples and 38% of voided urines from patients with bladder cancer. The integration of distribution patterns of clonal allelic losses revealed by the microsatellite markers with those obtained by genotyping of SNPs disclosed that the loss within an approximately 4-Mb segment centered around RB1 may represent an incipient event in bladder neoplasia. However, the inactivation of RB1 occurred later and was associated with the onset of severe dysplasia/carcinoma in situ. Our studies provide evidence for the presence of critical alternative candidate genes mapping to the 13q14 region that are involved in clonal expansion of neoplasia within the bladder antecedent to the inactivation of the RB1 gene.

DOI10.1038/labinvest.3700378
Alternate JournalLab. Invest.
PubMed ID16402033
Grant ListP50 CA91846 / CA / NCI NIH HHS / United States
R01 CA66723 / CA / NCI NIH HHS / United States
U01 CA85078 / CA / NCI NIH HHS / United States