METHYLATION OF THE 5'-CPG ISLAND OF THE P16 CDKN2 TUMOR-SUPPRESSOR GENE IN NORMAL AND TRANSFORMED HUMAN TISSUES CORRELATES WITH GENE SILENCING/

Citation
M. Gonzalezzulueta et al., METHYLATION OF THE 5'-CPG ISLAND OF THE P16 CDKN2 TUMOR-SUPPRESSOR GENE IN NORMAL AND TRANSFORMED HUMAN TISSUES CORRELATES WITH GENE SILENCING/, Cancer research, 55(20), 1995, pp. 4531-4535
Citations number
32
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
55
Issue
20
Year of publication
1995
Pages
4531 - 4535
Database
ISI
SICI code
0008-5472(1995)55:20<4531:MOT5IO>2.0.ZU;2-1
Abstract
Loss of heterozygosity on 9p21, where the p16/CDKN2 tumor suppressor a nd the p15(INK4B) cell cycle regulator genes are located, is a common genetic alteration in bladder cancer. However, it has been difficult t o demonstrate homozygous deletions and intragenic mutations in either of these two genes in primary transitional cell carcinomas (TCC) of th e bladder. Similarly, colon cancer-derived cell lines have shown no ho mozygous deletions of the p16/CDKN2 locus in contrast to a wide variet y of tumor-derived cell lines. We have investigated abnormal methylati on of the 5' CpG islands of the p16/CDKN2 and p15(INK4B) genes as an a lternative mechanism of inactivation of these genes in bladder and col on cancers. De novo methylation of the 5' CpG island of p16/CDKN2 was observed in 12 of 18 (67%) uncultured bladder TCCs and in 2 of 3 (67%) bladder cell lines. In contrast, only 1 of 10 (10%) colon carcinomas showed methylation of the 5' CpG island of p16/CDKN2. It was striking to find that this region was extensively methylated and the gene not e xpressed in the normal colonic mucosa of 6 of 10 (60%) patients with c olon cancer, whereas 5 of the corresponding colon tumors showed no met hylation and high levels of p16/CDKN2 expression. Our data show a sign ificant correlation (P = 0.00001, two-sided) between the absence of p1 6/CDKN2 expression and methylation of its 5' CpG island in bladder tum ors, cell lines, and normal colon mucosa. In contrast, no association was observed between expression and methylation status of the 5' CpG i sland of p15(INK4B). Our results suggest that the p16/CDKN2 tumor supp ressor gene may be inactivated by methylation of its 5' CpG island in TCCs of the bladder. We also present evidence of methylation of the 5' CpG island in this autosomal gene in normal colonic tissue.