Division of Molecular Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Gut. 2010 Sep;59(9):1236-44. doi: 10.1136/gut.2009.195701. Epub 2010 May 17.
Liver metastases are the leading cause of death in colorectal cancer. To gain better insight into the biology of metastasis and possibly identify new therapeutic targets we systematically investigated liver-metastasis-specific molecular aberrations.
Primary colorectal cancer (pCRC) and matched liver metastases (LMs) from the same patients were analysed by microarray-based comparative genomic hybridisation in 21 pairs and gene expression profiling in 18 pairs. Publicly available databases were used to confirm findings in independent datasets.
Chromosome aberration patterns and expression profiles of pCRC and matched LMs were strikingly similar. Unsupervised cluster analysis of genomic data showed that 20/21 pairs were more similar to each other than to any other analysed tumour. A median of only 11 aberrations per patient was found to be different between pCRC and LM, and expression of only 16 genes was overall changed upon metastasis. One region on chromosome band 11p15.5 showed a characteristic gain in LMs in 6/21 patients. This gain could be confirmed in an independent dataset of LMs (n=50). Localised within this region, the growth factor IGF2 (p=0.003) and the intestinal stem cell specific transcription factor ASCL2 (p=0.029) were found to be over-expressed in affected LM. Several ASCL2 target genes were upregulated in this subgroup of LM, including the intestinal stem cell marker OLFM4 (p=0.013). The correlation between ASCL2 expression and four known direct transcriptional targets (LGR5, EPHB3, ETS2 and SOX9) could be confirmed in an independent expression dataset (n=50).
With unprecedented resolution a striking conservation of genomic alterations was demonstrated in liver metastases, suggesting that metastasis typically occurs after the pCRC has fully matured. In addition, we characterised a subset of liver metastases with an ASCL2-related stem-cell signature likely to affect metastatic behaviour of tumour cells.
肝转移是结直肠癌患者死亡的主要原因。为了深入了解转移的生物学特性，并可能发现新的治疗靶点，我们系统地研究了肝转移特异性的分子异常。
通过微阵列比较基因组杂交分析了 21 对原发性结直肠癌（pCRC）及其匹配的肝转移灶（LM），并对 18 对进行了基因表达谱分析。使用公共数据库在独立数据集验证发现。
pCRC 和匹配的 LM 的染色体畸变模式和表达谱非常相似。基因组数据的无监督聚类分析表明，20/21 对彼此之间的相似性大于与任何其他分析肿瘤的相似性。每个患者只有 11 个异常被发现存在于 pCRC 和 LM 之间的差异，并且转移后只有 16 个基因的表达总体上发生改变。在 6/21 例患者的 LM 中，11p15.5 染色体带的一个区域表现出特征性的获得。这一增益可以在 LM 的一个独立数据集（n=50）中得到证实。在这个区域内，生长因子 IGF2（p=0.003）和肠干细胞特异性转录因子 ASCL2（p=0.029）被发现过度表达于受影响的 LM 中。在这个 LM 亚组中，多个 ASCL2 靶基因上调，包括肠干细胞标志物 OLFM4（p=0.013）。在一个独立的表达数据集（n=50）中，可以证实 ASCL2 表达与四个已知的直接转录靶基因（LGR5、EPHB3、ETS2 和 SOX9）之间的相关性。
具有前所未有的分辨率，本研究证明了肝转移中基因组改变的惊人保守性，这表明转移通常发生在 pCRC 完全成熟之后。此外，我们描述了一个具有 ASCL2 相关干细胞特征的肝转移亚组，这可能影响肿瘤细胞的转移行为。
