Deletion of the p16 and p15 genes in human bladder tumors

Orlow, I., Lacombe, L., Hannon, G. J., Serrano, M., Pellicer, I., Dalbagni, G., Reuter, V. E., Zhang, Z. F., Beach, D., Cordon-Cardo, C. (1995) Deletion of the p16 and p15 genes in human bladder tumors. Journal of the National Cancer Institute, 87 (20). pp. 1524-1529. ISSN 00278874 (ISSN)

DOI: 10.1093/jnci/87.20.1524


Background: Two genes, p16 (also known as CDKN2, INK4A, or MTSI) and p15 (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 p16 and p15 genes occurs frequently in cancer cell lines and in certain malignant neoplasms. Purpose: We evaluated the frequency of p16 and p15 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 p16 and p15 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 p16 and the p15 genes was observed in 11 and nine bladder tumors, respectively. Eight of the 11 tumors exhibiting complete loss of the p16 gene also displayed homozygous deletion of the p15 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 p16 and/or p15 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} = 11.1%-25.6%] of 109 informative tumors for the p16 gene and in 18 [18%, 95% CI = 10.5%-25.5%] of 100 informative tumors for the p15 gene). A statistically significant association between p16 gene alteration and bladder tumors of low stage (P<.01) and grade (P<.01) was observed; a significant association between p15 gene alteration and tumors of low stage (P<.01) was also detected. Conclusions: Alteration of the p16 and p15 genes, especially coincident homozygous deletion, appears to be a common event in bladder cancer.

Item Type: Paper
Uncontrolled Keywords: article bladder tumor carcinogenesis chromosome 9p controlled study gene deletion human human tissue transitional cell carcinoma tumor suppressor gene Aged Base Sequence Bladder Neoplasms Blotting, Southern Carcinoma, Transitional Cell Chromosomes, Human, Pair 9 Cyclin-Dependent Kinases Female Gene Rearrangement Genes, Tumor Suppressor Heterozygote Homozygote Male Middle Age Molecular Sequence Data Polymerase Chain Reaction Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.
Subjects: diseases & disorders > cancer > cancer types > bladder cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
organism description > animal > mammal > primates > hominids > human
CSHL Authors:
Communities: CSHL labs > Beach lab
CSHL labs > Hannon lab
Depositing User: Jessica Koos
Date: 1995
Date Deposited: 11 Aug 2014 20:25
Last Modified: 11 Aug 2014 20:25
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