© 1995 by Oxford University Press
Journal of the National Cancer Institute, Vol. 87, No. 20, 1524-1529,
October 18, 1995
© 1995 Oxford University Press
Deletion of the p16 and p15 Genes in Human Bladder Tumors
Memorial Sloan-Kettering Cancer Center New York
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory Cold Spring Harbor, NY
*Correspondence to: Carlos Cordon-Cardo, M.D., Ph.D., Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
BACKGROUND:: Two genes, pl6 (also known as CDKN2, INK4A, or MTS1) and pl5 (also described as INK4B or MTS2), are found in tandem at chromosome 9p21. These genes are designated as candidate tumor suppressor genes because they encode proteins that function as negative cell cycle regulators. (The encoded polypeptides inactivate specific cyclin-protein kinase complexes that are required for progression through the cell cycle.) Molecular genetic studies have revealed that deletion of the pl6 and pl5 genes occurs frequently in cancer cell lines and in certain malignant neoplasms.
PURPOSE:: We evaluated the frequency of pl6 and pl5 gene alterations in a well-characterized cohort of human transitional cell bladder cancers, and we explored potential associations between alterations in these genes and tumor stage and/or grade.
METHODS:: Tumor tissue and normal tissue from 110 patients with transitional cell carcinoma of the urinary bladder were examined. The status of the pl6 and pl5 genes in these tissues was determined by Southern blotting and hybridization with gene-specific probes, by coupled polymerase chain reaction and single-strand conformation polymorphism analysis (PCR-SSCP), and by sequencing DNA fragments produced during PCR. Associations between alterations in the genes and tumor stage and/or grade were evaluated using the two-tailed Fisher's exact test.
RESULTS:: Homozygous deletion (both alleles lost) of the pl6 and the pl5 genes was observed in 11 and nine bladder tumors, respectively. Eight of the 11 tumors exhibiting complete loss of the pl6 gene also displayed homozygous deletion of the pl5 gene. Exclusive loss of either gene was detected in only three tumors. Hemizygous deletion (one allele lost, also referred to as loss of heterozygosity [LOH]) of the pl6 and/or pl5 genes was observed in eight tumors. Rearrangement of the two genes was indicated in three additional tumors. No point mutations were identified in either gene. The overall frequency of alteration in this cohort of bladder tumors was approximately 18% for each gene (in 20 [18.3%, 95% confidence interval {CI} = ll.l%-25.6%] of 109 informative tumors for the pl6 gene and in 18 [18%, 95% CI = 10.5-25.5%] of 100 informative tumors for the pl5 gene). A statistically significant association between pl6 gene alteration and bladder tumors of low stage (P<.01) and grade (P<.01) was observed; a significant association between pl5 gene alteration and tumors of low stage (P<.01) was also detected.
CONCLUSIONS:: Alteration of the pl6 and pl5 genes, especially coincident homozygous deletion, appears to be a common event in bladder cancer. [J Natl Cancer Inst 1995;87:1524–9]
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