title: Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia.
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.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.forename: Joon
authors.initials: J
authors.lastname: Jeong
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Majewski
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kram
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Yoon
authors.forename: Ruo-Dan
authors.initials: RD
authors.lastname: Zhang
authors.forename: Jun-Zhi
authors.initials: JZ
authors.lastname: Li
authors.forename: Konrad
authors.initials: K
authors.lastname: Ptaszynski
authors.forename: Tang C
authors.initials: TC
authors.lastname: Kuang
authors.forename: Jain-Hua
authors.initials: JH
authors.lastname: Zhou
authors.forename: Ubaradka G
authors.initials: UG
authors.lastname: Sathyanarayana
authors.forename: Tomasz
authors.initials: T
authors.lastname: Tuziak
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Johnston
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Grossman
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Steven E
authors.initials: SE
authors.lastname: Scherer
authors.forename: William F
authors.initials: WF
authors.lastname: Benedict
authors.forename: Bogdan
authors.initials: B
authors.lastname: Czerniak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D019175:DNA Methylation; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D016160:Retinoblastoma Protein