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p53 Gene and Protein Status: The Role of p53 Alterations in Predicting Outcome in Patients With Bladder Cancer

Ben George, Ram H. Datar, Lin Wu, Jie Cai, Nancy Patten, Stephen J. Beil, Susan Groshen, John Stein, Donald Skinner, Peter A. Jones, Richard J. Cote

From the Departments of Pathology, Urology, Preventive Medicine, and Biochemistry, University of Southern California, Keck School of Medicine, Los Angeles; and Roche Molecular Systems, Pleasanton, CA

Address reprint requests to Richard J. Cote, MD, FRCPath, Department of Pathology and Urology, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, NOR 2424, Los Angeles, CA 90033; e-mail cote_r{at}ccnt.usc.edu

Purpose: The p53 gene status (mutation) and protein alterations (nuclear accumulation detectable by immunohistochemistry; p53 protein status) are associated with bladder cancer progression. Substantial discordance is documented between the p53 protein and gene status, yet no studies have examined the relationship between the gene-protein status and clinical outcome. This study evaluated the clinical relationship of the p53 gene and protein statuses.

Materials and Methods: The complete coding region of the p53 gene was queried using DNA from paraffin-embedded tissues and employing a p53 gene–sequencing chip. We compared p53 gene status, mutation site, and protein status with time to recurrence.

Results: The p53 gene and protein statuses show significant concordance, yet 35% of cases showed discordance. Exon 5 mutations demonstrated a wild-type protein status in 18 of 22 samples. Both the p53 gene and protein statuses were significantly associated with stage and clinical outcome. Specific mutation sites were associated with clinical outcome; tumors with exon 5 mutations showed the same outcome as those with the wild-type gene. Combining the p53 gene and protein statuses stratifies patients into three distinct groups, based on recurrence-free intervals: patients showing the best outcome (wild-type gene and unaltered protein), an intermediate outcome (either a mutated gene or an altered protein) and the worst outcome (a mutated gene and an altered protein).

Conclusion: We show that evaluation of both the p53 gene and protein statuses provides information in assessing the clinical recurrence risk in bladder cancer and that the specific mutation site may be important in assessing recurrence risk. These findings may substantially impact the assessment of p53 alterations and the management of bladder cancer.

Supported in part by Grants No. NCI CA 70903, NCI CA 14089, and NCI PO1 CA 86871 from the National Cancer Institute.

B.G. and R.H.D. share first authorship.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Editorial

• p53: It Has It All, But Will It Make It to the Clinic As a Marker in Bladder Cancer?
  Francisco X. Real
  JCO 2007 25: 5341-5344 [Full Text]

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				p53 in Bladder Cancer: The Next Chapter Journal Watch Oncology and Hematology, December 18, 2007; 2007(1218): 4 - 4. [Full Text]

				F. X. Real p53: It Has It All, But Will It Make It to the Clinic As a Marker in Bladder Cancer? J. Clin. Oncol., December 1, 2007; 25(34): 5341 - 5344. [Full Text] [PDF]