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(American Journal of Pathology. 1999;155:105-113.)
© 1999 American Society for Investigative Pathology

Regular Articles

Deletions of the INK4A Gene in Superficial Bladder Tumors

Association with Recurrence

Irene Orlow^*, Helene LaRue, Iman Osman, Louis Lacombe, Lynne Moore^§, Farhang Rabbani^¶, François Meyer^§, Yves Fradet and Carlos Cordon-Cardo^*

From the Department of Pathology,^*
Department of Medicine,
and Urology Service,^¶
Memorial Sloan-Kettering Cancer Center, New York, New York and the Laboratoire d'Uro-Oncologie Expérimentale
and Groupe de Recherche en Épidémiologie,^§
Centre de Recherche en Cancérologie de l'Université Laval, Québec, Canada

The INK4A and the INK4B genes map to chromosome 9p21, an area frequently deleted in bladder neoplasms. In addition to the p16 protein, the INK4A encodes for a second product, termed p19^ARF. We analyzed tissues from 121 patients with initial Ta and T1 tumors. Deletions of the INK4A gene were observed in 17 of 121 (14.1%) cases. Point mutations were identified in 2 of 64 (3.1%) tumors. The INK4A-exon 1ß and the INK4B gene were codeleted with INK4A in all of the homozygously deleted cases analyzed. The p16 promoter underwent de novo methylation in 7 of 47 (14.9%) evaluable cases. The p16-positive phenotype was observed in 18 of 56 (32%) evaluable cases. p16 negative phenotype correlated with deletion and methylation status. A statistically significant association between INK4A homozygous deletions and tumor size was observed (P = 0.003). Patients bearing tumors with INK4A homozygous deletions had a lower recurrence-free survival (P = 0.040) than those with wild type INK4A. In conclusion, deletions and methylation of the INK4A gene occur frequently in superficial bladder tumors. However, only those deletions that affect both the p16 and the p19^ARF, deregulating both the pRb and p53 pathways, correlated with clinicopathological parameters of worse prognosis.

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