Kang Ji Un, Koo Sun Hoe, Kwon Kye Chul, Park Jong Woo, Kim Jin Man
Department of Laboratory Medicine, Chungnam National University Hospital, Daesa-dong 640, Taejeon City 301-721, Korea.
Cancer Genet Cytogenet. 2008 Apr 1;182(1):1-11. doi: 10.1016/j.cancergencyto.2007.12.004.
Chromosomal imbalances resulting in altered gene dosage play a role in the molecular pathogenesis of non-small cell lung cancer (NSCLC), but the target genes remain to be identified. To identify early-stage genetic events that drive progression of NSCLC, we conducted a high-resolution array comparative genomic hybridization (CGH) study, using an array of 4,046 bacterial artificial chromosome clones to screen for DNA copy number changes associated with individual genes in 36 tumors obtained from patients in early stages of NSCLC. Multiple early genetic events occurring on chromosome 5p were identified, with a minimal detection region at 5p15.33 approximately 12. The most frequent finding involved gain of 5p15.33, observed in 15 of 19 stage I (A+B) cancers (79%) and in 28 of the total 36 NSCLC cases (78%). This locus harbors the genes TERT, SLC6A19, and SLC6A18 and is a telomeric boundary at bacterial artificial chromosome (BAC) clone 91_J20. Other potential candidate genes evidencing high numbers of genomic copy number changes (> or =40% of patients) included the following genes, encountered in >50% of 19 stage I (A+B) cancers: CEP72 and TPPP (14 of 19; 74%); AHRR, EXOC3 (previously SEC6L1), SLC9A3, LOC442126, ZDHHC11, BRD9, and TRIP13 (13/19; 68%); and CLPTM1L (alias CRR9), SLC6A3 (previously DAT1), and LOC401169 (10/19; 53%). Fluorescence in situ hybridization validated the array CGH findings. The gain of 5p15.33 is thus one of the most consistent alterations in the early stages of lung cancer, and a series of genes in the critical 5p15.33 region may be used as novel biomarkers for the early detection and classification of lung cancer.
导致基因剂量改变的染色体失衡在非小细胞肺癌（NSCLC）的分子发病机制中起作用，但目标基因仍有待确定。为了确定驱动NSCLC进展的早期遗传事件，我们进行了一项高分辨率阵列比较基因组杂交（CGH）研究，使用包含4046个细菌人工染色体克隆的阵列来筛选与从NSCLC早期患者获得的36个肿瘤中单个基因相关的DNA拷贝数变化。在5号染色体短臂上发现了多个早期遗传事件，最小检测区域位于5p15.33，约为12。最常见的发现是5p15.33的扩增，在19例I期（A+B）癌症中的15例（79%）以及36例NSCLC病例中的28例（78%）中观察到。该位点包含TERT、SLC6A19和SLC6A18基因，并且是细菌人工染色体（BAC）克隆91_J20处的端粒边界。其他显示大量基因组拷贝数变化（≥患者的40%）的潜在候选基因包括以下基因，在19例I期（A+B）癌症的50%以上中出现：CEP72和TPPP（19例中的14例；74%）；AHRR、EXOC3（以前的SEC6L1）、SLC9A3、LOC442126、ZDHHC11、BRD9和TRIP13（13/19；68%）；以及CLPTM1L（别名CRR9）、SLC6A3（以前的DAT1）和LOC401169（10/19；53%）。荧光原位杂交验证了阵列CGH的结果。因此，5p15.33的扩增是肺癌早期最一致的改变之一，关键的5p15.33区域中的一系列基因可作为肺癌早期检测和分类的新型生物标志物。
