Gene discovery in bladder cancer progression using cDNA microarrays

Marta Sanchez-Carbayo, Nicholas D. Socci, Juan Jose Lozano, Wentian Li, Elizabeth Charytonowicz, Thomas J. Belbin, Michael B. Prystowsky, Angel R. Ortiz, Geoffrey J. Childs, Carlos Cordon-Cardo

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

To identify gene expression changes along progression of bladder cancer, we compared the expression profiles of early-stage and advanced bladder tumors using cDNA microarrays containing 17,842 known genes and expressed sequence tags. The application of bootstrapping techniques to hierarchical clustering segregated early-stage and invasive transitional carcinomas into two main clusters. Multidimensional analysis confirmed these clusters and more importantly, it separated carcinoma in situ from papillary superficial lesions and subgroups within early-stage and invasive tumors displaying different overall survival. Additionally, it recognized early-stage tumors showing gene profiles similar to invasive disease. Different techniques including standard t-test, single-gene logistic regression, and support vector machine algorithms were applied to identify relevant genes involved in bladder cancer progression. Cytokeratin 20, neuropilin-2, p21, and p33ING1 were selected among the top ranked molecular targets differentially expressed and validated by immunohistochemistry using tissue microarrays (n = 173). Their expression patterns were significantly associated with pathological stage, tumor grade, and altered retinoblastoma (RB) expression. Moreover, p33ING1 expression levels were significantly associated with overall survival. Analysis of the annotation of the most significant genes revealed the relevance of critical genes and pathways during bladder cancer progression, including the overexpression of oncogenic genes such as DEK in superficial tumors or immune response genes such as Cd86 antigen in invasive disease. Gene profiling successfully classified bladder tumors based on their progression and clinical outcome. The present study has identified molecular biomarkers of potential clinical significance and critical molecular targets associated with bladder cancer progression.

Original languageEnglish (US)
Pages (from-to)505-516
Number of pages12
JournalAmerican Journal of Pathology
Volume163
Issue number2
StatePublished - Aug 1 2003

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Genetic Association Studies
Oligonucleotide Array Sequence Analysis
Urinary Bladder Neoplasms
Genes
Cluster Analysis
Neoplasms
CD86 Antigens
Neuropilin-2
Keratin-20
Critical Pathways
Retinoblastoma
Expressed Sequence Tags
Carcinoma in Situ
Biomarkers
Logistic Models
Immunohistochemistry
Carcinoma
Gene Expression

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Sanchez-Carbayo, M., Socci, N. D., Lozano, J. J., Li, W., Charytonowicz, E., Belbin, T. J., ... Cordon-Cardo, C. (2003). Gene discovery in bladder cancer progression using cDNA microarrays. American Journal of Pathology, 163(2), 505-516.

Gene discovery in bladder cancer progression using cDNA microarrays. / Sanchez-Carbayo, Marta; Socci, Nicholas D.; Lozano, Juan Jose; Li, Wentian; Charytonowicz, Elizabeth; Belbin, Thomas J.; Prystowsky, Michael B.; Ortiz, Angel R.; Childs, Geoffrey J.; Cordon-Cardo, Carlos.

In: American Journal of Pathology, Vol. 163, No. 2, 01.08.2003, p. 505-516.

Research output: Contribution to journalArticle

Sanchez-Carbayo, M, Socci, ND, Lozano, JJ, Li, W, Charytonowicz, E, Belbin, TJ, Prystowsky, MB, Ortiz, AR, Childs, GJ & Cordon-Cardo, C 2003, 'Gene discovery in bladder cancer progression using cDNA microarrays', American Journal of Pathology, vol. 163, no. 2, pp. 505-516.
Sanchez-Carbayo M, Socci ND, Lozano JJ, Li W, Charytonowicz E, Belbin TJ et al. Gene discovery in bladder cancer progression using cDNA microarrays. American Journal of Pathology. 2003 Aug 1;163(2):505-516.
Sanchez-Carbayo, Marta ; Socci, Nicholas D. ; Lozano, Juan Jose ; Li, Wentian ; Charytonowicz, Elizabeth ; Belbin, Thomas J. ; Prystowsky, Michael B. ; Ortiz, Angel R. ; Childs, Geoffrey J. ; Cordon-Cardo, Carlos. / Gene discovery in bladder cancer progression using cDNA microarrays. In: American Journal of Pathology. 2003 ; Vol. 163, No. 2. pp. 505-516.
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