p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer

Abstract

The p16 gene has been identified as a candidate tumour suppressor gene at 9p21, a region commonly deleted in bladder cancer. We screened 140 bladder tumours and 16 cell lines for deletions and sequence variants of p16. Eight cell lines showed homozygous deletion of p16 and two had small sequence variations. All 13 tumours with small defined deletions of 9p21, 18/31 (58%) of tumours with monosomy 9 and 9/91 (10%) of tumours with no chromosome 9 loss of heterozygosity had homozygous deletion of p16. No tumour-specific sequence variants were identified. Deletion mapping revealed a nested set of deletions focused on p16. Six deletions involved p16 but not the related and adjacent gene p15 and one tumour had an intragenic deletion of p16. All other deletions involved both p16 and p15. We conclude that p16 represents the major target for deletion at 9p21 in bladder cancer.

Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer

“…The MTS 1 gene was postulated as a potential major target of allelic losses involving the p21 region in bladder cancer (Williamson et al, 1995). Others indicate that LOH on p21 less frequently results in the absence of functional MTs 1 product in bladder cancer (Packenham et al, 1995;Orlow et al, 1995).…”

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

“…This possibility has been based on the fact that LOH of 9p21 is common in bladder cancers, but homozygous deletion and mutation directly e ecting the MTS-1 gene is much less frequent (Cairns et al, 1994;Spruck et al, 1994;Packenham et al, 1995;Orlow et al, 1995). Nevertheless, others have suggested not only that p16 loss of function is a common event in bladder cancer, but also that it is the major target for deletion at 9p21 in bladder cancer (Williamson et al, 1995).…”

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

“…We have previously identified two bladder tumor cell lines in which p16 exon 2 is deleted but a marker R2.7 34 now known to be between p16 and CDKN2A exon 1␤ is retained, suggesting that exon 1␤ is also retained. 15 A germline deletion of p14 ARF but not CDKN2A exon 1␣ has been reported in a melanomaneural system syndrome family. 35 Similarly, deletion of exon 1␤ has been detected in a sporadic melanoma patient 36 in two melanoma cell lines 37 and three acute lymphocytic leukemia samples.…”

“…21 A third mechanism of inactivation, transcriptional silencing by promoter hypermethylation, is commonly found in colorectal carcinoma. 22 Point mutations have only rarely been identified in bladder tumors 15,23,24 and promoter methylation, only infrequently. 25 Since the discovery of p14 ARF , 14 much interest has centered on the relative involvement of p16 and p14 ARF as tumor suppressor genes in both mouse models and in human cancer.…”

“…Homozygous deletions at CDKN2A/9p21 are common in bladder tumors 6,[15][16][17] and have been described in a variety of other sporadic tumors, including melanomas 18 and gliomas. 19 Pancreatic adenocarcinomas show inactivation of CDKN2A by either homozygous deletion or point mutation, 20 whereas esophageal tumors commonly show inactivation by point mutation.…”