Inactivation of the CDKN2/p16/MTSJ Gene Is Frequently Associated with Aberrant DNA Methylation in All Common Human Cancers'

The tumor suppressor gene CDKN2/p16/MTSI,located on chromosome 9p21, is frequenfly inactivated in many human cancers through homozy gous 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 lsland ls 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 neoplasla.