Hamada K, Kohno T, Kawanishi M, Ohwada S, Yokota J
Biology Division, National Cancer Center Research Institute, Tokyo, Japan.
Genes Chromosomes Cancer. 1998 Jul;22(3):232-40. doi: 10.1002/(sici)1098-2264(199807)22:3<232::aid-gcc9>3.0.co;2-x.
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.
为了阐明9号染色体短臂上存在多个肿瘤抑制基因的可能性，我们对CDKN2A/p16/MTS1和CDKN2B/p15/MTS2基因进行了遗传和表观遗传学分析，并对人肺癌中的9p进行了纯合缺失定位。为避免因非癌细胞污染而忽略基因改变，我们检测了32个非小细胞肺癌（NSCLC）细胞系和16个小细胞肺癌（SCLC）细胞系。（在32个NSCLC细胞系中的20个（63%）中，CDKN2A发生了突变或纯合缺失，在携带野生型CDKN2A基因的12个细胞系中的6个中检测到了CDKN2A基因中CpG岛的甲基化。虽然在CDKN2A缺失的NSCLC细胞系中也检测到了CDKN2B基因的纯合缺失，但CDKN2B基因的突变和甲基化并不常见。因此，表明CDKN2A基因而非CDKN2B基因在NSCLC中作为肿瘤抑制基因发挥关键作用。在14个（44%）NSCLC细胞系中检测到9p上的纯合缺失。值得注意的是，在CDKN2A和CDKN2B基因座近端定位到了两个常见的纯合缺失区域，这表明9p上存在除CDKN2A之外的肿瘤抑制基因。与NSCLC相反，9p上的纯合缺失以及CDKN2A和CDKN2B的改变在SCLC中并不常见。因此，9p改变的发病机制意义在SCLC和NSCLC之间可能有所不同。
