Association of CDKN2A(p16)/CDKN2B(p15) alterations and homozygous chromosome arm 9p deletions in human lung carcinoma.

To elucidate the possibility of the existence of multiple tumor suppressor genes on chromosome arm 9p, we performed genetic and epigenetic analyses of the CDKN2A/p16/MTS1 and CDKN2B/p15/MTS2 genes as well as homozygous deletion mapping of 9p in human lung carcinoma. To avoid overlooking genetic alterations due to contamination of noncancerous cells, we examined 32 non-small cell lung carcinoma (NSCLC) and 16 cell small cell lung carcinoma (SCLC) cell lines. (CDKN2A was mutated or homozygously deleted in 20 (63%) of 32 NSCLC cell lines, and methylation of the CpG island in the CDKN2A gene was detected in six of the 12 cell lines carrying the wild-type CDKN2A gene. Although homozygous deletions of the CDKN2B gene were also detected in NSCLC cell lines with CDKN2A deletions, mutation and methylation in the CDKN2B gene were infrequent. Thus, it was indicated that the CDKN2A gene rather than the CDKN2B gene plays a critical role as a tumor suppressor gene in NSCLC. Homozygous deletions on 9p were detected in 14 (44%) NSCLC cell lines. It is of note that two common regions of homozygous deletions were mapped proximal to the CDKN2A and CDKN2B loci, suggesting that tumor suppressor genes other than CDKN2A are present on 9p. In contrast to NSCLC, homozygous deletions on 9p as well as CDKN2A and CDKN2B alterations were infrequent in SCLC. Therefore, the pathogenetic significance of 9p alterations is likely to differ between SCLC and NSCLC.