Division of Multistep Carcinogenesis, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Genes Chromosomes Cancer. 2013 Sep;52(9):802-16. doi: 10.1002/gcc.22076. Epub 2013 May 28.
To obtain a landscape of gross genetic alterations in small cell lung cancer (SCLC), genome-wide copy number analysis and whole-transcriptome sequencing were performed in 58 and 42 SCLCs, respectively. Focal amplification of known oncogene loci, MYCL1 (1p34.2), MYCN (2p24.3), and MYC (8q24.21), was frequently and mutually exclusively detected. MYCL1 and MYC were co-amplified with other regions on either the same or the different chromosome in several cases. In addition, the 9p24.1 region was identified as being amplified in SCLCs without amplification of MYC family oncogenes. Notably, expression of the KIAA1432 gene in this region was significantly higher in KIAA1432 amplified cells than in non-amplified cells, and its mRNA expression showed strong correlations with the copy numbers. Thus, KIAA1432 is a novel gene activated by amplification in SCLCs. By whole-transcriptome sequencing, a total of 60 fusion transcripts, transcribed from 95 different genes, were identified as being expressed in SCLC cells. However, no in-frame fusion transcripts were recurrently detected in ≥2 SCLCs, and genes in the amplified regions, such as PVT1 neighboring MYC and RLF in MYCL1 amplicons, were recurrently fused with genes in the same amplicons or with those in different amplicons on either the same or different chromosome. Thus, it was indicated that amplification and fusion of several genes on chromosomes 1 and 8 occur simultaneously but not sequentially through chromothripsis in the development of SCLC, and amplification rather than fusion of genes plays an important role in its development.
为了获得小细胞肺癌（SCLC）的总体遗传改变图谱，分别对 58 例和 42 例 SCLC 进行了全基因组拷贝数分析和全转录组测序。频繁且相互排斥地检测到已知癌基因座 MYCL1（1p34.2）、MYCN（2p24.3）和 MYC（8q24.21）的局灶性扩增。在几种情况下，MYCL1 和 MYC 与同一或不同染色体上的其他区域同时或分别被扩增。此外，9p24.1 区域被鉴定为在没有 MYC 家族癌基因扩增的 SCLC 中被扩增。值得注意的是，该区域中 KIAA1432 基因的表达在 KIAA1432 扩增细胞中明显高于非扩增细胞，其 mRNA 表达与拷贝数呈强相关性。因此，KIAA1432 是 SCLC 中扩增激活的一个新基因。通过全转录组测序，总共鉴定出 60 个融合转录本，由 95 个不同的基因转录而来，这些转录本在 SCLC 细胞中表达。然而，没有在≥2 例 SCLC 中反复检测到框架内融合转录本，并且在扩增区域中的基因，如 MYC 附近的 PVT1 和 MYCL1 扩增子中的 RLF，与相同扩增子或同一或不同染色体上不同扩增子中的基因反复融合。因此，这表明在 SCLC 的发展过程中，染色体 1 和 8 上的几个基因的扩增和融合是同时发生的，而不是通过染色体重排依次发生的，并且基因的扩增而不是融合在其发展中起着重要作用。
