Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering.
Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering.
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发表时间：
2000-09
期刊：
影响因子：
11.2
通讯作者：
L. Girard;S. Zöchbauer-Müller;A. Virmani;A. Gazdar;J. Minna
中科院分区：
文献类型：
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作者：
L. Girard;S. Zöchbauer-Müller;A. Virmani;A. Gazdar;J. Minna
为了确定主要的肿瘤抑制基因（TSG）位点参与肺癌的发病机制，我们进行了高分辨率（10 cM），全基因组杂合性缺失（洛）的搜索。在ABI 377测序仪/基因分型仪上，使用来自ABI Prism连锁图谱集v.2的399个荧光微卫星标记分析了36个肺癌细胞系[14个小细胞肺癌（SCLC）和22个非SCLC（NSCLC）]及其匹配的对照DNA。总体而言，确定了22个具有超过60%洛缺失的不同区域：（a）13个区域偏好SCLC;（B）7个区域偏好NSCLC;和（c）2个区域同时影响SCLC和NSCLC。洛丢失频率最高的染色体臂为1 p、3 p、4p、4 q、5 q、8 p、9 p（p16）、9 q、10 p、10 q、13 q（Rb）、15 q、17 p（p53）、18 q、19 p、Xp、Xq。此外，在2 p23、8 q24、18 q11和Xq 22处发现了新的纯合缺失。平均而言，34%（SCLC）至36%（NSCLC）的标记物在个体肿瘤中显示等位基因丢失，亚染色体区域丢失的平均大小为5至6个标记物（50-60 cM）。尽管SCLC和NSCLC具有不同的频繁洛（热点）区域，并且NSCLC的这些区域（n = 22）比SCLC（n = 17）更多，但在所有其他参数（等位基因丢失分数、断裂点数量和微卫星改变数量）中，SCLC和NSCLC没有显著差异。聚类分析揭示了不同染色体上的洛缺失之间的相关性，提示了以前未知的肺癌发生的遗传相互作用。我们的结论是：（a）在肺癌细胞系中，至少有17-22个染色体区域涉及频繁的等位基因丢失，这表明相同数量的推定TSG被失活;（B）SCLC和NSCLC经常发生不同的特异性遗传改变;（c）TSG簇可能一起失活。总的来说，这些数据提供了导致肺癌的遗传变化程度的全球估计，并将有助于新TSGs的定位克隆和用于转化研究的多个新生物标志物的鉴定。
To identify the major tumor suppressor gene (TSG) loci involved in the pathogenesis of lung cancer, we have conducted a high-resolution (10 cM), genome-wide search of loss of heterozygosity (LOH). Thirty-six lung cancer cell lines [14 small cell lung cancers (SCLCs) and 22 non-SCLCs (NSCLCs)] and their matched control DNAs were analyzed using 399 fluorescent microsatellite markers from the ABI Prism linkage mapping set v.2 on an ABI 377 sequencer/genotyper. Overall, 22 different regions with more than 60% LOH were identified: (a) 13 regions with a preference for SCLC; (b) 7 regions with a preference for NSCLC; and (c) 2 regions affecting both SCLC and NSCLC. The chromosomal arms with the most frequent LOH were 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16), 9q, 10p, 10q, 13q (Rb), 15q, 17p (p53), 18q, 19p, Xp, Xq. In addition, new homozygous deletions were found at 2p23, 8q24, 18q11, and Xq22. On average, 34% (SCLC) to 36% (NSCLC) of markers showed allele loss in individual tumors, with an average size of subchromosomal region of loss of five to six markers (50-60 cM). Whereas SCLC and NSCLC had different regions of frequent LOH (hot spots), and NSCLC had more of these regions (n = 22) than SCLC (n = 17), in all other parameters (fractional allelic loss, number of breakpoints, and number of microsatellite alterations), SCLC and NSCLC were not significantly different. Clustering analysis revealed correlations between LOH on different chromosomes that suggest previously unknown genetic interactions for lung cancer development. We conclude that (a) in lung cancer cell lines, at least 17-22 chromosomal regions with frequent allele loss are involved, suggesting that the same number of putative TSGs are inactivated; (b) SCLC and NSCLC frequently undergo different specific genetic alterations; and (c) clusters of TSGs are likely to be inactivated together. Overall, these data provide global estimates of the extent of genetic changes leading to lung cancer and will be useful for the positional cloning of new TSGs and for the identification of multiple new biomarkers for translational research.