ROLE OF THE P16 TUMOR-SUPPRESSOR GENE IN CANCER

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1 993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespre ad importance in cancer. The frequent mutations and deletions of p16 i n human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significa ntly strengthened by the observation that p16 was frequently inactivat ed in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neopla sms, p16 is silenced in at least three ways: homozygous deletion, meth ylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. A dditionally, the loss of p16 may be an early event in cancer progressi on, because deletion of at least one copy is quite high in some premal ignant lesions. p16 is a major target in carcino genesis, rivaled in f requency only by the p53 tumor-suppressor gene, Its mechanism of actio n as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, an d thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and res ults in cell-cycle arrest. Although p16 may be involved in cell senesc ence, the physiologic role of p16 is still unclear. Future work will f ocus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic s trategies that can improve the clinical course of many lethal cancers, (C) 1998 by American Society of Clinical Oncology.