Both copies of the candidate tumor suppressor gene on chromosome 9, CDKN2, are deleted in approximately one-fourth of lung cancer cell lines examined and the protein product of CDKN2, p16 is undetectable in one-third of the lung cancer cell lines studied.
However, the relative frequency of homozygous CDKN2 deletions in non-small-cell lung cancers (NSCLC) and in small-cell lung cancers (SCLC) has not been determined.
To examine its tumor suppressive function and its potential in cancer gene replacement therapy, wild-type p16INK4 was expressed in an adenovirus-derived gene delivery system and introduced into lung cancer cell lines that do not express p16INK4.
We have examined 88 lung cancer lines for p16INK4 protein expression and have observed a striking inverse correlation between the presence of p16INK4 and wildtype RB.
In summary, inactivation of CDKN2 is implicated in the development of about 20% of NSCLC, but the possibility of another tumor suppressor gene on chromosome segment 9p21 important in lung cancercannot be eliminated.
We examined the expression of p16 and Rb protein by means of immunohistochemistry in 61 non-small cell lung cancers and have demonstrated an inverse relationship between the expression of p16 and Rb protein: 28/30 specimens that did not stain for p16 stained for Rb and 21/31 p16-positive specimens did not stain for Rb.
Although the frequency of mutations in the p16/CDKN2 gene has been detected in approximately 30% of non-small cell lung cancer, loss of heterozygosity on 9p has been observed in greater than 70% of non-small cell lung cancers.
Furthermore, rat lung cancer appears to be an excellent model in which to investigate the mechanisms of de novo gene methylation and the role of p16 dysfunction in the progression of neoplasia.
Western blot analysis showed that the expression of both NM23 and MTS1 proteins was reduced in human lung cancer CH27 cells by retinoic acid treatment, but the ratio of NM23: MTS1 increased in a dose-dependent manner.
In contrast, cancer cell lines which were wild-type for p16 but mutant or null for pRb (Saos-2, C33a and H358) were <threefold more sensitive to Adp16 when compared to a control virus.
Since somatic mutations of the p53, RB and p16 genes occur frequently in lung cancer and the replication error phenotype is seen in a subset of lung cancer, it is possible that germ-line mutations of the p53, RB, p16 and mismatch repair genes influence the susceptibility to lung cancer.