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Presence and Location of TP53 Mutation Determines Pattern of CDKN2A/ARF Pathway Inactivation in Bladder Cancer¹

Department of Biochemistry and Molecular Biology, Urologic Cancer Research Laboratory, USC/Norris Comprehensive Cancer Center, University of Southern California, School of Medicine, Los Angeles, California 90033

Transformation and immortalization require the inactivation of key cell cycle regulatory genes. We examined 19 bladder cancer cell lines derived from 17 patients for alterations in TP53, RB1, CDKN2A, and ARF. Twelve cell lines had a mutation in exons 5–11 of TP53 and, with only one exception, a concomitant loss of RB1 protein expression. Another group of seven cell lines had a wild-type TP53 gene or a mutation in exons 1–4 of TP53 and concomitant alterations in both CDKN2A and ARF in every case. This demonstrates the requirement, in all but one line, for inactivation of both the CDKN2A/RB1 and ARF/TP53 pathways in bladder cancer cell lines and provides the first evidence for potential differences in the penetrance of mutations in the transactivation and DNA-binding domains of TP53.

¹ This work was supported by USPHS Grant 5 R35 CA49758-10 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 816, Mail Stop #83, Los Angeles, CA 90033. Phone: (323) 865-0816; Fax: (323) 865-0102.

Received 9/ 8/98. Accepted 10/19/98.

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