Neiman P E, Kimmel R, Icreverzi A, Elsaesser K, Bowers S-J, Burnside J, Delrow J
Division of Basic Science, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA 98109-1024, USA.
Oncogene. 2006 Oct 12;25(47):6325-35. doi: 10.1038/sj.onc.1209646. Epub 2006 May 1.
Retroviral vector-mediated overexpression of c-myc in embryonic bursal precursors induces multi-staged tumorigenesis beginning with preneoplastic-transformed follicles (TF) and progressing to clonal metastatic B-cell lymphomas. Using a 13K chicken cDNA microarray, specifically enriched for chicken immune system expressed sequence tagged (ESTs), we carried out array-based comparative genomic hybridization (array-CGH) and detected significant DNA copy number change at many loci on most or all chromosomes in both early TF and end-stage lymphomas. Formation of long palindromes, through breakage-fusion-bridge cycles, is thought to play an early role in gene amplification. Employing genome-wide analysis of palindrome formation (GAPF), we detected extensive palindrome formation in early TF and end-stage lymphomas. The population of loci showing amplification by array-CGH was enriched for palindromes detected by GAPF providing strong evidence for genetic instability early in Myc-induced tumorigenesis and further support for the role of palindromes in gene amplification. Comparing gene copy number change and RNA expression changes profiled on the same cDNA array, we detected very little consistent contribution of gene copy number change to RNA expression changes. Palindromic loci in TF and tumors, however, were expressed, many at high levels, suggesting an abundance of RNA species with long double-stranded segments generated during tumorigenesis.
逆转录病毒载体介导的胚胎法氏囊前体细胞中c-myc的过表达会诱导多阶段肿瘤发生，始于癌前转化滤泡（TF），并进展为克隆性转移性B细胞淋巴瘤。我们使用一个专门富集鸡免疫系统表达序列标签（EST）的13K鸡cDNA微阵列，进行了基于阵列的比较基因组杂交（array-CGH），并在早期TF和终末期淋巴瘤的大多数或所有染色体上的许多位点检测到显著的DNA拷贝数变化。通过断裂-融合-桥循环形成长回文结构，被认为在基因扩增中起早期作用。通过全基因组回文结构形成分析（GAPF），我们在早期TF和终末期淋巴瘤中检测到广泛的回文结构形成。通过array-CGH显示扩增的位点群体富含通过GAPF检测到的回文结构，这为Myc诱导的肿瘤发生早期的遗传不稳定性提供了有力证据，并进一步支持了回文结构在基因扩增中的作用。比较在同一cDNA阵列上分析的基因拷贝数变化和RNA表达变化，我们检测到基因拷贝数变化对RNA表达变化的一致贡献非常小。然而，TF和肿瘤中的回文位点是表达的，许多表达水平很高，这表明在肿瘤发生过程中产生了大量具有长双链片段的RNA种类。
