High-resolution whole-organ mapping with SNPs and its significance to early events of carcinogenesis.
We attempted to identify deleted segments in two model tumor suppressor gene loci on chromosomes 13q14 and 17p13 that were associated with clonal expansion of in situ bladder preneoplasia using single nucleotide polymorphisms (SNPs)-based whole-organ histologic and genetic mapping. For mapping with SNPs, the sequence-based maps spanning approximately 27 and 5 Mb centered around RB1 and p53, respectively, were assembled. The integrated gene and SNP maps of the regions were used to select 661 and 960 SNPs, which were genotyped by pyrosequencing. Genotyping of SNPs was performed on DNA samples corresponding to histologic maps of the entire bladder mucosa in human cystectomy specimens with invasive urothelial carcinoma. By using this approach, we have identified deleted regions associated with clonal expansion of intraurothelial neoplasia; which ranged from 0.001 to 4.3 Mb (average 0.67 Mb) and formed clusters of discontinuous deleted segments. The high resolution of such maps is a prerequisite for future positional targeting of genes involved in early phases of bladder neoplasia. This approach also permits analysis of the overall genomic landscape of the involved region and discloses that a unique composition of noncoding DNA characterized by a high concentration of repetitive sequences may predispose to deletions.
Tuziak
Tomasz
T
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jeong
Joon
J
Majewski
Tadeusz
T
Kim
Mi-Sook
MS
Steinberg
Jordan
J
Wang
Zhi
Z
Yoon
Dong-Sup
DS
Kuang
Tang C
TC
Baggerly
Keith
K
Johnston
Dennis
D
Czerniak
Bogdan
B
D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D002886:Chromosomes, Human, Pair 17; D002999:Clone Cells / Q000473:pathology; D004273:DNA, Neoplasm / Q000032:analysis; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D016160:Retinoblastoma Protein / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000378:metabolism / Q000473:pathology
D004273:DNA, Neoplasm; D016160:Retinoblastoma Protein