Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy

• Published in: Laboratory investigation Vol. 88; no. 7; pp. 694 - 721
• Main Authors: Majewski, Tadeusz, Lee, Sangkyou, Jeong, Joon, Yoon, Dong-Sup, Kram, Andrzej, Kim, Mi-Sook, Tuziak, Tomasz, Bondaruk, Jolanta, Lee, Sooyong, Park, Weon-Seo, Tang, Kuang S, Chung, Woonbok, Shen, Lanlan, Ahmed, Saira S, Johnston, Dennis A, Grossman, H Barton, Dinney, Colin P, Zhou, Jain-Hua, Harris, R Alan, Snyder, Carrie, Filipek, Slawomir, Narod, Steven A, Watson, Patrice, Lynch, Henry T, Gazdar, Adi, Bar-Eli, Menashe, Wu, Xifeng F, McConkey, David J, Baggerly, Keith, Issa, Jean-Pierre, Benedict, William F, Scherer, Steven E, Czerniak, Bogdan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2008; Nature Publishing; Nature Publishing Group
• Subjects: Aged; Biological and medical sciences; Biotechnology; Bladder cancer; Carcinoma, Transitional Cell - genetics; Chromosome Mapping; Chromosomes, Human, Pair 13 - genetics; Fundamental and applied biological sciences. Psychology; Humans; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Microsatellite Repeats; Middle Aged; Pathology; Polymorphism, Single Nucleotide; research-article; Retinoblastoma Protein - genetics; Urinary Bladder - metabolism; Urinary Bladder - pathology; Urinary Bladder Neoplasms - genetics; Urothelium - metabolism; Urothelium - pathology; high-resolution mapping with SNPs; dual-track pathway of bladder cancer development; apoptosis; forerunner genes; whole-organ histologic and genetic mapping; Biotechnology; High resolution; Genomics; Carcinogenesis; Gene; Clinical biology; Development; Genetics; Genetic mapping; Human; Cartography; Urinary system disease; Chromosome; Histology; Urinary tract disease; Malignant tumor; Bladder cancer; Cell death; Strategy; Bladder disease; Genome; Cancer; Apoptosis; Organ
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2008.27

The search for the genomic sequences involved in human cancers can be greatly facilitated by maps of genomic imbalances identifying the involved chromosomal regions, particularly those that participate in the development of occult preneoplastic conditions that progress to clinically aggressive invasive cancer. The integration of such regions with human genome sequence variation may provide valuable clues about their overall structure and gene content. By extension, such knowledge may help us understand the underlying genetic components involved in the initiation and progression of these cancers. We describe the development of a genome-wide map of human bladder cancer that tracks its progression from in situ precursor conditions to invasive disease. Testing for allelic losses using a genome-wide panel of 787 microsatellite markers was performed on multiple DNA samples, extracted from the entire mucosal surface of the bladder and corresponding to normal urothelium, in situ preneoplastic lesions, and invasive carcinoma. Using this approach, we matched the clonal allelic losses in distinct chromosomal regions to specific phases of bladder neoplasia and produced a detailed genetic map of bladder cancer development. These analyses revealed three major waves of genetic changes associated with growth advantages of successive clones and reflecting a stepwise conversion of normal urothelial cells into cancer cells. The genetic changes map to six regions at 3q22–q24, 5q22–q31, 9q21–q22, 10q26, 13q14, and 17p13, which may represent critical hits driving the development of bladder cancer. Finally, we performed high-resolution mapping using single nucleotide polymorphism markers within one region on chromosome 13q14, containing the model tumor suppressor gene RB1 , and defined a minimal deleted region associated with clonal expansion of in situ neoplasia. These analyses provided new insights on the involvement of several non-coding sequences mapping to the region and identified novel target genes, termed forerunner (FR) genes, involved in early phases of cancer development.