Homozygous deletions but no sequence mutations in coding regions of p15 or p16 in human primary bladder tumors

Abstract

Chromosome 9p21 appears to harbor a tumor suppressor gene, as evidenced by deletions in this region in a variety of human primary tumors and cell lines. To map the deletion at 9p21 in bladder tumors, we analyzed DNA from 28 tumor and normal pairs at five microsatellite markers that flank the region occupied by the putative tumor suppressor genes p16 and p15. Loss of heterozygosity (LOH) at the markers human interferon (HIFN) alpha and D9S171, which are adjacent to the p15 and p16 loci, was detected in 41% and 33%, respectively, of informative cases of bladder tumors. No sequence mutations were detected in exons 1 or 2 of either p15 or p16 in any of the bladder tumors. Three sequence-tagged site markers in the region bordered by HIFN alpha and D9S171 were used to further map the deleted region by multiplex polymerase chain reaction with the HIFN gamma maker (on chromosome 12) as a control for amplification. Six of 11 tumors with LOH at surrounding markers had homozygous deletions of the marker c5.1, which is located within the p16 gene; and two tumors appeared to have homozygous deletions within p15 (RN1.1) but not p16 (c5.1). A recently identified microsatellite marker, p16-CA-1, located 16 kb distal to p16, proved valuable in defining the minimal deletion involved in these bladder tumors. Five tumors exhibited homozygous deletions of this marker but not HIFN alpha and two tumors showed LOH at this marker and homozygous deletion of p16. Although these data could not be used to identify p16 or p15 as the definitive tumor suppressor gene in this region that is involved in bladder carcinogenesis, they suggest that homozygous deletion is a common mechanism of loss of tumor suppressor gene function in this region.

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

“…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). It appears that the frequency of the MTS 1 gene involvement in TCC is much lower than that reported for cell lines (Cairns et al, 1994;Spruck et al, 1994).…”

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

“…The existence of one or more additional tumor suppressor genes on 9p21 has also been suggested by others. 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).…”

Mechanisms of p16INK4A inactivation in non small-cell lung cancers

“…Homozygous deletions have been described in lung tumors, with a highly variable frequency (9 ± 25%). They were more frequently detected in cell lines (Kamb et al, 1994;Nobori et al, 1994) than in fresh tumor tissue (Cairns et al, 1995;Packenham et al, 1995;De Vos et al, 1995;Marchetti et al, 1997;Wiest et al, 1997) probably due to stromal contamination of the tumoral samples. Methylation of the 5' CpG island associated with transcriptional silencing has been investigated in only one study of primary lung tumors where its incidence was 26% .…”