Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Stange
D E
DE
Division of Molecular Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Engel
F
F
Longerich
T
T
Koo
B K
BK
Koch
M
M
Delhomme
N
N
Aigner
M
M
Toedt
G
G
Schirmacher
P
P
Lichter
P
P
Weitz
J
J
Radlwimmer
B
B
D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D016678:Genome / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D051792:Basic Helix-Loop-Helix Proteins; D007335:Insulin-Like Growth Factor II; C065501:ASCL2 protein, human; C035170:IGF2 protein, human