Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification
Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification
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DOI：
10.1038/sj.onc.1208997
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Pollack, JR
中科院分区：
文献类型：
--
作者：
Kim, YH;Girard, L;Pollack, JR
DNA扩增和缺失经常导致肺癌的发生和发展。为了确定小细胞肺癌(SCLC)中这种新的改变，我们对一组24个小细胞肺癌细胞系进行了比较基因组杂交，使用了代表22,000个人类基因的cDNA微阵列(提供了70kb的平均图谱分辨率)。我们鉴定了定位的DNA扩增。与已知在小细胞肺癌中扩增的癌基因对应的阳离子，包括MYC(8q24)、MYCN(2p24)和MYCL1(1p34)。额外的高度本地化的DNA扩增。阳离子提示了先前未发现在小细胞肺癌中扩增的候选癌基因，包括抗凋亡基因TNFRSF4(1p36)、DAD1(14q11)、BCL2L1(20q11)和BCL2L2(14q11)。同样，新发现的经PCR验证的纯合子缺失提示候选抑癌基因，包括促凋亡基因MAPK10(4q21)和TNFRSF6(10q23)。目的：研究DNA扩增的作用。阳离子对基因的表达模式，我们进行了表达PRO。Ling使用相同的微阵列平台。在我们的发现中，我们发现了一组基因，它们的表达与MYC、MYCN或MYCL1扩增相关，令人惊讶的是，基因组之间几乎没有重叠。而MYC和MYCN扩增。阳离子分别与已知的MYC上调和下调靶基因的表达增加和降低有关，MYCL1扩增仅与后者相关。我们的。研究结果支持细胞凋亡平衡改变在小细胞肺癌发病机制中的作用，并提示MYC家族基因可能通过不同的靶点影响肿瘤的发生，特别是暗示转录抑制的重要性。
DNA amplifications and deletions frequently contribute to the development and progression of lung cancer. To identify such novel alterations in small cell lung cancer (SCLC), we performed comparative genomic hybridization on a set of 24 SCLC cell lines, using cDNA microarrays representing similar to 22 000 human genes (providing an average mapping resolution of < 70 kb). We identified localized DNA amplifi. cations corresponding to oncogenes known to be amplified in SCLC, including MYC (8q24), MYCN (2p24) and MYCL1 (1p34). Additional highly localized DNA amplifi. cations suggested candidate oncogenes not previously identified as amplifified in SCLC, including the antiapoptotic genes TNFRSF4 (1p36), DAD1 (14q11), BCL2L1 (20q11) and BCL2L2 (14q11). Likewise, newly discovered PCR-validated homozygous deletions suggested candidate tumor-suppressor genes, including the proapoptotic genes MAPK10 (4q21) and TNFRSF6 (10q23). To characterize the effect of DNA amplifi. cation on gene expression patterns, we performed expression pro. ling using the same microarray platform. Among our findings, we identified sets of genes whose expression correlated with MYC, MYCN or MYCL1 amplification, with surprisingly little overlap among gene sets. While both MYC and MYCN ampli. cation were associated with increased and decreased expression of known MYC upregulated and downregulated targets, respectively, MYCL1 amplification was associated only with the latter. Our. findings support a role of altered apoptotic balance in the pathogenesis of SCLC, and suggest that MYC family genes might affect oncogenesis through distinct sets of targets, in particular implicating the importance of transcriptional repression.