Tsafrir Dafna, Bacolod Manny, Selvanayagam Zachariah, Tsafrir Ilan, Shia Jinru, Zeng Zhaoshi, Liu Hao, Krier Curtis, Stengel Robert F, Barany Francis, Gerald William L, Paty Philip B, Domany Eytan, Notterman Daniel A
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
Cancer Res. 2006 Feb 15;66(4):2129-37. doi: 10.1158/0008-5472.CAN-05-2569.
Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples.
多项研究已证实结肠癌中存在多种染色体异常。然而，在疾病进展过程中，DNA拷贝数与基因表达之间的关系尚未得到充分探索，也未进行全面监测。在这项研究中，我们从大量处于疾病不同阶段的结肠癌患者中收集了三种类型的阵列生成数据（表达数据、单核苷酸多态性数据和比较基因组杂交数据）。将探针注释到特定的染色体位置，并揭示了特定位置上DNA拷贝数和转录水平的协同变化。我们发现，在基因组的许多大区域中，表达水平的变化与DNA含量的改变相关。通常，包含多个基因的大染色体片段会受到协同的转录影响，并且我们表明其潜在机制是DNA含量的相应变化。这意味着，虽然特定的染色体异常可能是随机出现的，但部分或所有受影响基因表达的相关变化会促使携带这些异常的细胞进行克隆扩增。实际上，在原发性结肠肿瘤中，特定的染色体区域经常出现获得和过表达（例如7p、8q、13q和20q）或缺失和低表达（例如1p、4、5q、8p、14q、15q和18），这使得这些变化可能有利于肿瘤发生。此外，我们发现这些畸变在正常结肠黏膜中不存在，在良性腺瘤中出现（尽管仅在一小部分样本中），随着疾病进展变得更加频繁，并且在大多数转移样本中也能发现。
