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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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