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p14ARF Promoter Hypermethylation in Plasma DNA as an Indicator of Disease Recurrence in Bladder Cancer Patients¹

Departments of Medical Oncology [G. D., J. S., J. M. S., J. M. G., M. P., P. E., F. B.], Urology [J. C.], and Pathology [J. M.], Clínica Puerta de Hierro, E-28035 Madrid, Spain

Purpose: Several genes are reported to be implicated in bladder carcinogenesis, including p53, p16INK4a, pRb, erbB-2, Cyclin D1, H-ras, EGFR, and c-myc. Gene alterations in plasma DNA identical to those observed within the tumor have been detected in various types of neoplasia.

Experimental Design: We analyzed loss of heterozygosity in six microsatellite markers (D17S695, D17S654, D13S310, TH2, D9S747, and D9S161), p53 and K-ras mutations, and the promoter status of p14ARF and p16INK4a in the mononuclear normal blood cells, tumor, and plasma DNA of 27 bladder cancer patients. We also studied the distribution of several clinicopathological parameters in these patients in regard to molecular alterations.

Results: Seventeen (63%) cases displayed the same alteration in plasma and tumor DNA (some patients showed more than one alteration simultaneously). Plasma p14ARF promoter hypermethylation was associated with the presence of multicentric foci (P = 0.03), larger tumors (P = 0.01), and relapse of the disease (P = 0.03). Plasma loss of heterozygosity was also linked to disease recurrence (P = 0.02).

Conclusions: The results indicate that p14ARF aberrant promoter methylation could be involved in bladder carcinogenesis and that plasma DNA is a potential prognostic marker in urinary bladder cancer.

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