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Methylation of the 5' CpG Island of the p16/CDKN2 Tumor Suppressor Gene in Normal and Transformed Human Tissues Correlates with Gene Silencing¹

Urological Research Laboratory, USC/Norris Comprehensive Cancer Center [M. G-Z., C. M. B., A. S. Y., T. N., J. M. V., P. A. J.], and Department of Colorectal Surgery [R. W. B.], University of Southern California, School of Medicine, Los Angeles, California 90033

Loss of heterozygosity on 9p21, where the p16/CDKN2 tumor suppressor and the p15^INK4B cell cycle regulator genes are located, is a common genetic alteration in bladder cancer. However, it has been difficult to demonstrate homozygous deletions and intragenic mutations in either of these two genes in primary transitional cell carcinomas (TCC) of the bladder. Similarly, colon cancer-derived cell lines have shown no homozygous deletions of the p16/CDKN2 locus in contrast to a wide variety of tumor-derived cell lines. We have investigated abnormal methylation of the 5' CpG islands of the p16/CDKN2 and p15^INK4B genes as an alternative mechanism of inactivation of these genes in bladder and colon 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 expressed in the normal colonic mucosa of 6 of 10 (60%) patients with colon cancer, whereas 5 of the corresponding colon tumors showed no methylation and high levels of p16/CDKN2 expression. Our data show a significant correlation (P = 0.00001, two-sided) between the absence of p16/CDKN2 expression and methylation of its 5' CpG island in bladder tumors, cell lines, and normal colon mucosa. In contrast, no association was observed between expression and methylation status of the 5' CpG island of p15^INK4B. Our results suggest that the p16/CDKN2 tumor suppressor 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.

¹ Supported by USPHS Grant R35CA49758 from the National Cancer Institute.

² To whom requests requests for reprints should be addressed, at USC/Norris Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033. Phone: (213) 764-0816; Fax: (213) 764-0102.

Received 6/20/95. Accepted 8/30/95.

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				I. P. de Castro, M. Malumbres, J. Santos, A. Pellicer, and J. Fernandez-Piqueras Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas Carcinogenesis, September 1, 1999; 20(9): 1675 - 1682. [Abstract] [Full Text] [PDF]

				A. S. Baur, P. Shaw, N. Burri, F. Delacretaz, F. T. Bosman, and P. Chaubert Frequent Methylation Silencing of p15INK4b (MTS2) and p16INK4a (MTS1) in B-Cell and T-Cell Lymphomas Blood, September 1, 1999; 94(5): 1773 - 1781. [Abstract] [Full Text] [PDF]

				D. J. Wong, S. A. Foster, D. A. Galloway, and B. J. Reid Progressive Region-Specific De Novo Methylation of the p16 CpG Island in Primary Human Mammary Epithelial Cell Strains during Escape from M0 Growth Arrest Mol. Cell. Biol., August 1, 1999; 19(8): 5642 - 5651. [Abstract] [Full Text] [PDF]

				S. Kawano, C. W. Miller, A. F. Gombart, C. R. Bartram, Y. Matsuo, H. Asou, A. Sakashita, J. Said, E. Tatsumi, and H. P. Koeffler Loss of p73 Gene Expression in Leukemias/Lymphomas Due to Hypermethylation Blood, August 1, 1999; 94(3): 1113 - 1120. [Abstract] [Full Text] [PDF]

				I. Orlow, H. LaRue, I. Osman, L. Lacombe, L. Moore, F. Rabbani, F. Meyer, Y. Fradet, and C. Cordon-Cardo Deletions of the INK4A Gene in Superficial Bladder Tumors : Association with Recurrence Am. J. Pathol., July 1, 1999; 155(1): 105 - 113. [Abstract] [Full Text] [PDF]

				J. K. Wiencke, S. Zheng, A. Lafuente, M. J. Lafuente, C. Grudzen, M. R. Wrensch, R. Miike, A. Ballesta, and M. Trias Aberrant Methylation of p16INK4a in Anatomic and Gender-specific Subtypes of Sporadic Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., June 1, 1999; 8(6): 501 - 506. [Abstract] [Full Text]

				C. T. Lee, P. Capodieci, I. Osman, M. Fazzari, J. Ferrara, H. I. Scher, and C. Cordon-Cardo Overexpression of the Cyclin-dependent Kinase Inhibitor p16 Is Associated with Tumor Recurrence in Human Prostate Cancer Clin. Cancer Res., May 1, 1999; 5(5): 977 - 983. [Abstract] [Full Text] [PDF]

				Q. Li, K. J. Kopecky, A. Mohan, C. L. Willman, F. R. Appelbaum, J. K. Weick, and J.-P. J. Issa Estrogen Receptor Methylation Is Associated with Improved Survival in Adult Acute Myeloid Leukemia Clin. Cancer Res., May 1, 1999; 5(5): 1077 - 1084. [Abstract] [Full Text] [PDF]

				W. D. Pennie, G. A. Hegamyer, M. R. Young, and N. H. Colburn Specific Methylation Events Contribute to the Transcriptional Repression of the Mouse Tissue Inhibitor of Metalloproteinases-3 Gene in Neoplastic Cells Cell Growth Differ., April 1, 1999; 10(4): 279 - 286. [Abstract] [Full Text]

				Y. Daigo, T. Nishiwaki, T. Kawasoe, M. Tamari, E. Tsuchiya, and Y. Nakamura Molecular Cloning of a Candidate Tumor Suppressor Gene, DLC1, from Chromosome 3p21.3 Cancer Res., April 1, 1999; 59(8): 1966 - 1972. [Abstract] [Full Text] [PDF]

				L. E. Lantry, Z. Zhang, K. A. Crist, Y. Wang, G. J. Kelloff, R. A. Lubet, and M. You 5-Aza-2'-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model Carcinogenesis, February 1, 1999; 20(2): 343 - 346. [Abstract] [Full Text] [PDF]

				I. Orlow, M. Drobnjak, Z.-F. Zhang, J. Lewis, J. M. Woodruff, M. F. Brennan, and C. Cordon-Cardo Alterations of INK4A and INK4B Genes in Adult Soft Tissue Sarcomas: Effect on Survival J Natl Cancer Inst, January 6, 1999; 91(1): 73 - 79. [Abstract] [Full Text] [PDF]

				I. H. N. Wong, Y. M. Dennis Lo, J. Zhang, C.-T. Liew, M. H. L. Ng, N. Wong, P. B. S. Lai, W. Y. Lau, N. M. Hjelm, and P. J. Johnson Detection of Aberrant p16 Methylation in the Plasma and Serum of Liver Cancer Patients Cancer Res., January 1, 1999; 59(1): 71 - 73. [Abstract] [Full Text] [PDF]

				E. P. Xing, Y. Nie, L.-D. Wang, G.-Y. Yang, and C. S. Yang Aberrant methylation of p16INK4a and deletion of p15INK4b are frequent events in human esophageal cancer in Linxian, China Carcinogenesis, January 1, 1999; 20(1): 77 - 84. [Abstract] [Full Text] [PDF]

				S. J. Kuerbitz, J. Malandro, N. Compitello, S. B. Baylin, and J. R. Graff Deletion of p16INK4A/CDKN2 and p15INK4B in Human Somatic Cell Hybrids and Hybrid-derived Tumors Cell Growth Differ., January 1, 1999; 10(1): 27 - 33. [Abstract] [Full Text]

				S. Y. Leung, S. T. Yuen, L. P. Chung, K. M. Chu, A. S. Y. Chan, and J. C. I. Ho hMLH1 Promoter Methylation and Lack of hMLH1 Expression in Sporadic Gastric Carcinomas with High-Frequency Microsatellite Instability Cancer Res., January 1, 1999; 59(1): 159 - 164. [Abstract] [Full Text] [PDF]

				A. Aggerholm, P. Guldberg, M. Hokland, and P. Hokland Extensive Intra- and Interindividual Heterogeneity of p15INK4B Methylation in Acute Myeloid Leukemia Cancer Res., January 1, 1999; 59(2): 436 - 441. [Abstract] [Full Text] [PDF]

				L. Chin, G. Merlino, and R. A. DePinho Malignant melanoma: modern black plague and genetic black box Genes & Dev., November 15, 1998; 12(22): 3467 - 3481. [Full Text]

				K. D. Robertson and P. A. Jones The Human ARF Cell Cycle Regulatory Gene Promoter Is a CpG Island Which Can Be Silenced by DNA Methylation and Down-Regulated by Wild-Type p53 Mol. Cell. Biol., November 1, 1998; 18(11): 6457 - 6473. [Abstract] [Full Text]

				M. L. Veigl, L. Kasturi, J. Olechnowicz, A. Ma, J. D. Lutterbaugh, S. Periyasamy, G.-M. Li, J. Drummond, P. L. Modrich, W. D. Sedwick, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers PNAS, July 21, 1998; 95(15): 8698 - 8702. [Abstract] [Full Text] [PDF]

				E. M. Swisher, D. G. Mutch, T. J. Herzog, J. S. Rader, L. D. Kowalski, A. Elbendary, and P. J. Goodfellow Analysis of MSH3 in Endometrial Cancers With Defective DNA Mismatch Repair Reproductive Sciences, July 1, 1998; 5(4): 210 - 216. [Abstract] [PDF]

				Y. E. Whang, X. Wu, H. Suzuki, R. E. Reiter, C. Tran, R. L. Vessella, J. W. Said, W. B. Isaacs, and C. L. Sawyers Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression PNAS, April 28, 1998; 95(9): 5246 - 5250. [Abstract] [Full Text] [PDF]

				S. Zhang, E. S. Ramsay, and B. A. Mock Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16INK4a and p19ARF, is a candidate for the plasmacytoma susceptibility locus, Pctr1 PNAS, March 3, 1998; 95(5): 2429 - 2434. [Abstract] [Full Text] [PDF]

				U. Klangby, I. Okan, K. P. Magnusson, M. Wendland, P. Lind, and K. G. Wiman p16/INK4a and p15/INK4b Gene Methylation and Absence of p16/INK4a mRNA and Protein Expression in Burkitt's Lymphoma Blood, March 1, 1998; 91(5): 1680 - 1687. [Abstract] [Full Text] [PDF]

				T. R. Yeager, S. DeVries, D. F. Jarrard, C. Kao, S. Y. Nakada, T. D. Moon, R. Bruskewitz, W. M. Stadler, L. F. Meisner, K. W. Gilchrist, et al. Overcoming cellular senescence in human cancer pathogenesis Genes & Dev., January 15, 1998; 12(2): 163 - 174. [Abstract] [Full Text]