Mechanisms of G(1) checkpoint loss in resected early stage non-small cell lung cancer

Loss of the G(1) checkpoint appears to be extremely common among virtually all neoplasms. A variety of genetic and epigenetic mechanisms have been dem onstrated to play significant roles in this process. In a consecutive serie s of early stage non-small cell lung cancer (NSCLC), we have established th e loss of expression of the G(1) Cdk inhibitors p15(INK4b) and p16(INK4a) b y DNA methylation is very common (37%), and methylation of p16(INK4a) is ti ghtly correlated with loss of expression of p16(INK4a) protein (P = 0.0018) . Furthermore, methylation of p16(INK4b) and p16(INK4a) appear inversely co rrelated, although methylation of p15(INK4b) is an infrequent event in this cohort (4%). Methylation was detected in all stages of NSCLC equally, and did not correlate with survival in these patients. Evidence for methylation was more frequent in squamous cell carcinomas in comparison to other tumor histologies (P = 0.0156). In addition, over-expression of cyclin D1 was fo und to be tightly restricted (P = 0.0032) to those tumors that had retained wild-type expression of pRB, and did not correlate with methylation or exp ression of p16(INK4a) gene product. Although loss of p16(INK4a) function re mains lightly correlated with pRB expression, loss of other regulatory elem ents in NSCLC such as p53 mutation and cyclin D1 over-expression appear ind ependent of loss of the p16(INK4a) gene product. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.