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Inactivation of the CDKN2/p16/MTS1 Gene Is Frequently Associated with Aberrant DNA Methylation in All Common Human Cancers¹

The Oncology Center [J. G. H., R. G. L., J-P. J. I., N. E. D., D. S., S. B. B.], Department of Medicine [S. B. B.], Baltimore, Maryland 21231, and Department of Otolaryngology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [A. M., L. M., D. S.]

The tumor suppressor gene CDKN2/p16/MTS1, located on chromosome 9p21, is frequently inactivated in many human cancers through homozygous deletion. Recently, we have reported another pathway of inactivation that involves loss of transcription associated with de novo methylation of a 5' CpG island of CDKN2/p16 in lung cancers, gliomas, and head and neck squamous cell carcinomas. We now show that this aberrant CpG island methylation also occurs frequently in cell lines of breast cancer (33%), prostate cancer (60%), renal cancer (23%), and colon cancer (92%) and is associated with loss of transcription. Primary tumors of the breast (31%) and colon (40%) also displayed de novo methylation of this CpG island. This alteration of p16 in colon cancer was particularly striking, since inactivation does not occur through homozygous deletion in this tumor type. Our data show that in tumors, de novo methylation of the 5' CpG island is a frequent mode of inactivation of CDKN2/p16 and also firmly demonstrate that CDKN2/p16 is one of the most frequently altered genes in human neoplasia.

¹ Supported by Grants CA54396 and CA43318. A. M. is the recipient of a Schweizensche Stiftung fur medizinish-biologishe Stipendien.

² To whom requests for reprints should be addressed, at Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231.

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

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				M van Rijnsoever, F Grieu, H Elsaleh, D Joseph, and B Iacopetta Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands Gut, December 1, 2002; 51(6): 797 - 802. [Abstract] [Full Text] [PDF]

				R. F. Newbold The significance of telomerase activation and cellular immortalization in human cancer Mutagenesis, November 1, 2002; 17(6): 539 - 550. [Abstract] [Full Text] [PDF]

				J. Goffin and E. Eisenhauer DNA methyltransferase inhibitors--state of the art Ann. Onc., November 1, 2002; 13(11): 1699 - 1716. [Abstract] [Full Text] [PDF]

				J. Zschocke, D. Manthey, N. Bayatti, B. van der Burg, S. Goodenough, and C. Behl Estrogen Receptor alpha -mediated Silencing of Caveolin Gene Expression in Neuronal Cells J. Biol. Chem., October 4, 2002; 277(41): 38772 - 38780. [Abstract] [Full Text] [PDF]

				Y. Li, H. Nagai, T. Ohno, M. Yuge, S. Hatano, E. Ito, N. Mori, H. Saito, and T. Kinoshita Aberrant DNA methylation of p57KIP2 gene in the promoter region in lymphoid malignancies of B-cell phenotype Blood, September 18, 2002; 100(7): 2572 - 2577. [Abstract] [Full Text] [PDF]

				T. Tokugawa, H. Sugihara, T. Tani, and T. Hattori Modes of Silencing of p16 in Development of Esophageal Squamous Cell Carcinoma Cancer Res., September 1, 2002; 62(17): 4938 - 4944. [Abstract] [Full Text] [PDF]

				J. M. Chapman, S. M. Knoepp, M. K. Byeon, K. W. Henderson, and C. W. Schweinfest The Colon Anion Transporter, Down-Regulated in Adenoma, Induces Growth Suppression That Is Abrogated by E1A Cancer Res., September 1, 2002; 62(17): 5083 - 5088. [Abstract] [Full Text] [PDF]

				Q N Vo, J Geradts, M L Gulley, D A Boudreau, J C Bravo, and B G Schneider Epstein-Barr virus in gastric adenocarcinomas: association with ethnicity and CDKN2A promoter methylation J. Clin. Pathol., September 1, 2002; 55(9): 669 - 675. [Abstract] [Full Text] [PDF]

				H. Tsuda, T. Takarabe, Y. Kanai, T. Fukutomi, and S. Hirohashi Correlation of DNA Hypomethylation at Pericentromeric Heterochromatin Regions of Chromosomes 16 and 1 with Histological Features and Chromosomal Abnormalities of Human Breast Carcinomas Am. J. Pathol., September 1, 2002; 161(3): 859 - 866. [Abstract] [Full Text] [PDF]

				M. J. Garcia, B. Martinez-Delgado, A. Cebrian, A. Martinez, J. Benitez, and C. Rivas Different Incidence and Pattern of p15INK4b and p16INK4a Promoter Region Hypermethylation in Hodgkin's and CD30-Positive Non-Hodgkin's Lymphomas Am. J. Pathol., September 1, 2002; 161(3): 1007 - 1013. [Abstract] [Full Text] [PDF]

				S.-W. Choi and J. B. Mason Folate Status: Effects on Pathways of Colorectal Carcinogenesis J. Nutr., August 1, 2002; 132(8): 2413S - 2418. [Abstract] [Full Text] [PDF]

				S. Toyooka, Y. Fukuyama, I. I. Wistuba, M. S. Tockman, J. D. Minna, and A. F. Gazdar Differential Expression of FEZ1/LZTS1 Gene in Lung Cancers and Their Cell Cultures Clin. Cancer Res., July 1, 2002; 8(7): 2292 - 2297. [Abstract] [Full Text] [PDF]

				N. Konishi, M. Nakamura, M. Kishi, M. Nishimine, E. Ishida, and K. Shimada Heterogeneous Methylation and Deletion Patterns of the INK4a/ARF Locus Within Prostate Carcinomas Am. J. Pathol., April 1, 2002; 160(4): 1207 - 1214. [Abstract] [Full Text] [PDF]

				L.-w. Tan, T. Bianco, and A. Dobrovic Variable promoter region CpG island methylation of the putative tumor suppressor gene Connexin 26 in breast cancer Carcinogenesis, February 1, 2002; 23(2): 231 - 236. [Abstract] [Full Text] [PDF]

				A. O.-O. Chan, J.-P. J. Issa, J. S. Morris, S. R. Hamilton, and A. Rashid Concordant CpG Island Methylation in Hyperplastic Polyposis Am. J. Pathol., February 1, 2002; 160(2): 529 - 536. [Abstract] [Full Text] [PDF]

				U. Lehmann, F. Langer, H. Feist, S. Glockner, B. Hasemeier, and H. Kreipe Quantitative Assessment of Promoter Hypermethylation during Breast Cancer Development Am. J. Pathol., February 1, 2002; 160(2): 605 - 612. [Abstract] [Full Text] [PDF]

				N. Bardeesy, J. Morgan, M. Sinha, S. Signoretti, S. Srivastava, M. Loda, G. Merlino, and R. A. DePinho Obligate Roles for p16Ink4a and p19Arf-p53 in the Suppression of Murine Pancreatic Neoplasia Mol. Cell. Biol., January 15, 2002; 22(2): 635 - 643. [Abstract] [Full Text] [PDF]

				J. S. Kang, B. F. Calvo, S. J. Maygarden, L. S. Caskey, J. L. Mohler, and D. K. Ornstein Dysregulation of Annexin I Protein Expression in High-Grade Prostatic Intraepithelial Neoplasia and Prostate Cancer Clin. Cancer Res., January 1, 2002; 8(1): 117 - 123. [Abstract] [Full Text] [PDF]