Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGH
Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGH
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DOI：
10.1002/gcc.20435
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发表时间：
2007-06-01
影响因子：
3.7
通讯作者：
Rabinovitch, Peter S.
中科院分区：
文献类型：
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作者：
Lai, Lisa A.;Paulson, Thomas G.;Rabinovitch, Peter S.
染色体不稳定被认为是肿瘤进展的潜在机制，是导致癌症的克隆选择和进化的组成部分。我们使用高分辨率Affymetrix定位100K SNP阵列评估了癌前Barrett‘s食道组织中的染色体不稳定性，患者经历了仅CDKN2A(LOH)、CDKN2A(LOH)/TP53(LOH)和CDKN2A(LOH)/TP53(LOH)三个分子阶段的非整倍体疾病。在个体内，随着时间的推移，我们观察到LOH或拷贝数变化的区域的数量和大小都有所增加。在最早的仅有CDKN2A(LOH)的样本中，我们检测到很少的区域既有拷贝改变又有LOH，而在更高级的样本中，拷贝丢失和LOH高度相关。这些数据表明，在肿瘤进展过程中，基因组的不稳定性增加了严重程度并改变了特征。此外，在巴雷特食道的一段内可以辨别出不同的克隆进化模式。总体而言，这项研究表明，癌前疾病可能与广泛的不稳定性和克隆动力学有关，这些不稳定性和克隆动力学从以基于重组的小改变为特征的初始阶段演变为可能与有丝分裂不稳定相关的较大拷贝改变事件。(C)2007年Wiley-Liss，Inc.
Chromosomal instability is regarded as an underlying mechanism of neoplastic progression, integral to the clonal selection and evolution that leads to cancer. We evaluated chromosomal instability in premalignant Barrett's esophagus tissue using high resolution Affymetrix mapping 100K SNP arrays as patients progressed through three molecular stages of disease CDKN2A(LOH) only, CDKN2A(LOH)/TP53(LOH), and CDKN2A(LOH)/TP53(LOH) with aneuploidy. Within individuals over time, we observed increases in both numbers and sizes of regions of LOH or copy number change. In the earliest CDKN2A(LOH) only samples, we detected few regions with both copy change and LOH, whereas copy loss and LOH were highly correlated in more advanced samples. These data indicate that genomic instability increases in severity and changes character during neoplastic progression. In addition, distinct patterns of clonal evolution could be discerned within a segment of Barrett's esophagus. Overall, this study illustrates that pre-malignant disease can be associated with extensive instability and clonal dynamics that evolve from an initial stage characterized by small recombination-based alterations to one with larger copy change events likely associated with mitotic instability. (c) 2007 Wiley-Liss, Inc.