Lai Lisa A, Paulson Thomas G, Li Xiaohong, Sanchez Carissa A, Maley Carlo, Odze Robert D, Reid Brian J, Rabinovitch Peter S
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
Genes Chromosomes Cancer. 2007 Jun;46(6):532-42. doi: 10.1002/gcc.20435.
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.
染色体不稳定被视为肿瘤进展的潜在机制，是导致癌症的克隆选择和进化所不可或缺的。随着患者经历疾病的三个分子阶段——仅CDKN2A（杂合性缺失）、CDKN2A（杂合性缺失）/TP53（杂合性缺失）以及伴有非整倍体的CDKN2A（杂合性缺失）/TP53（杂合性缺失），我们使用高分辨率Affymetrix 100K SNP基因分型芯片评估了癌前巴雷特食管组织中的染色体不稳定情况。在个体随时间的变化过程中，我们观察到杂合性缺失区域或拷贝数变化区域的数量和大小均有所增加。在最早仅出现CDKN2A（杂合性缺失）的样本中，我们检测到同时存在拷贝数变化和杂合性缺失的区域很少，而在更晚期的样本中，拷贝数丢失和杂合性缺失高度相关。这些数据表明，在肿瘤进展过程中，基因组不稳定的严重程度增加且特征发生变化。此外，在一段巴雷特食管中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态变化相关，这些变化从最初以基于小的重组改变为特征的阶段演变为一个具有可能与有丝分裂不稳定相关的更大拷贝数变化事件的阶段。
