Mapping and Genome Sequence Analysis of Chromosome 5 Regions Involved in Bladder Cancer Progression

We studied the evolution of allelic losses on chromosome 5 by whole-organ histologic and genetic mapping in 234 mucosal DNA samples of 5 cystectomy specimens with invasive bladder cancer and preneoplastic changes in adjacent urothelium. The frequency of alterations in individual loci was verified on 32 tumors and 29 voided urine samples from patients with bladder cancer. Finally, deleted regions on chromosome 5 were integrated with the human genome contigs and sequence-based databases. Deleted regions on chromosome 5 involved in intraurothelial phases of bladder neoplasia defined by their nearest flanking markers and predicted size were identified as follows: q13.3-q22 (D5S424-D5S656; 38.8 centimorgan [cM]); q22-q31.1 (D5S656-D5S808; 19.2 cM), q31.1-q32 (D5S816-SPARC; 11.5 cM), and q34 (GABRA1-D5S415; 6.4 cM). The two most frequently deleted neighbor markers (D5S2055 and D5S818) mapping to q22-q31.1 defined a 9 cM region, which may contain genes that play an important role in early phases of urinary bladder carcinogenesis. Human genome database analysis provided an accurate map of deleted regions with positions of 138 known genes and revealed several smaller gene-rich areas representing putative targets for further mapping. The strategic approach presented here, which combines whole-organ histologic and genetic mapping with analysis of the rapidly emerging human genome sequence database, facilitates identification of genes potentially involved in early phases of bladder carcinogenesis.

[1]  L. Sobin,et al.  Histological Typing of Urinary Bladder Tumours , 1999, International Histological Classification of Tumours.

[2]  M. von Knebel Doeberitz,et al.  Frequent allelic imbalance of tumor suppressor gene loci in cervical dysplasia. , 1999, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[3]  C. Reznikoff,et al.  Nonrandom chromosome losses in tumorigenic revertants of hybrids between isogeneic immortal and neoplastic human uroepithelial cells , 1991, Somatic cell and molecular genetics.

[4]  P. Lichter,et al.  Detection of chromosomal imbalances in transitional cell carcinoma of the bladder by comparative genomic hybridization. , 1995, The American journal of pathology.

[5]  I. Wieland,et al.  Deletion analysis at the DEL‐27, APC and MTS1 loci in bladder cancer: LOH at the DEL‐27 locus on 5p13‐12 is a prognostic marker of tumor progression , 1997, International journal of cancer.

[6]  I. Wistuba,et al.  Genetic changes in the spectrum of neuroendocrine lung tumors , 1999, Cancer.

[7]  B. Czerniak,et al.  Superimposed histologic and genetic mapping of chromosome 17 alterations in human urinary bladder neoplasia , 1997, Oncogene.

[8]  A. Jauch,et al.  Allelic changes at multiple regions of chromosome 5 are associated with progression of urinary bladder cancer , 2000, The Journal of pathology.

[9]  A. Sandberg,et al.  A possible specific chromosome change in transitional cell carcinoma of the bladder. , 1986, Cancer genetics and cytogenetics.

[10]  M. Spence,et al.  Analysis of human genetic linkage , 1986 .

[11]  D. Carter.  TNM Classification of Malignant Tumors , 1998 .

[12]  T. Taniguchi,et al.  Functionally inactivating point mutation in the tumor‐suppressor IRF‐1 gene identified in human gastric cancer , 1998, International journal of cancer.

[13]  J. Epstein,et al.  Partial allelotype of carcinoma in situ of the human bladder. , 1995, Cancer research.

[14]  M. Wigler,et al.  Detecting gene copy number fluctuations in tumor cells by microarray analysis of genomic representations. , 2000, Genome research.

[15]  Taylor Murray,et al.  Cancer statistics, 2000 , 2000, CA: a cancer journal for clinicians.

[16]  D. Teng,et al.  Localization of SMAD5 and its evaluation as a candidate myeloid tumor suppressor. , 1997, Cancer research.

[17]  L. Koss,et al.  Mapping cancerous and precancerous bladder changes. A study of the urothelium in ten surgically removed bladders. , 1974, JAMA.

[18]  R. Simon,et al.  Chromosomal aberrations associated with invasion in papillary superficial bladder cancer. , 1999, The Journal of pathology.

[19]  H. Grossman,et al.  Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer , 1999, Oncogene.

[20]  Richard A. Szucs,et al.  TNM Classification of Malignant Tumors. 5th ed , 1998 .

[21]  V. Gorgoulis,et al.  Allelic imbalance at the 5q14 locus is associated with decreased apoptotic rate in non-small cell lung carcinomas (NSCLCs). Possible synergistic effect with p53 gene alterations on apoptosis. , 2000, Lung cancer.

[22]  A. Gazdar,et al.  Filling the void: urinary markers for bladder cancer risk and diagnosis. , 2001, Journal of the National Cancer Institute.

[23]  R. Cote,et al.  Two molecular pathways to transitional cell carcinoma of the bladder. , 1994, Cancer research.

[24]  John A. Hartigan,et al.  Clustering Algorithms , 1975 .

[25]  Leopold G. Koss,et al.  Diagnostic Cytology of the Urinary Tract : With Histopathologic and Clinical Correlations , 1996 .

[26]  B. Czerniak,et al.  Genetic modeling of human urinary bladder carcinogenesis , 2000, Genes, chromosomes & cancer.

[27]  O. Yoshida,et al.  Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. , 1998, Cancer research.

[28]  Ash A. Alizadeh,et al.  Genome-wide analysis of DNA copy-number changes using cDNA microarrays , 1999, Nature Genetics.

[29]  C. Cordon-Cardo,et al.  Genetic alterations in bladder cancer , 1993, The Lancet.

[30]  M. Fox,et al.  5q deletion. The sole chromosome change in a carcinoma of the bladder. , 1990, Cancer genetics and cytogenetics.

[31]  C. Ihm,et al.  Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. , 1999, Cancer genetics and cytogenetics.