Overexpression of E2F-1 in Lung and Liver Metastases of Human Colon Cancer is Associated with Gene Amplification

We have shown previously that metastatic tumors of human colorectal cancer (CRC) in lung as compared to liver have high levels of thymidylate synthase (TS) mRNA expression correlated with high levels of E2F-1 mRNA expression. We now report that Comparative Genomic Hybridization (CGH) and DNA PCR analyses of lung and liver metastases of human colon cancer show frequent gains in the region of chromosome 20q and have an increase in gene copy number of E2F-1. Six of 48 lung and liver metastases of human CRC (12.5%) had less than or equal to 1.5 fold increase in gene copies while the remainder (87.5%) had greater than 1.5 fold increase. The mean fold increase in E2F-1 gene copy number in the primary CRC samples (2.76, n=9) is lower than that seen in the metastatic CRC tumors (mean value 3.5 fold, n=48). Primary CRC tumors had significantly higher gene copy number for E2F-1 (mean E2F-1 gene copy number was 2.76 fold, n=9) than matched adjacent normal (mean =2.16, n=9, p=0.06 using paired t test). In as much as TS is transcriptionally regulated by E2F-1, these results provide an explanation for the high levels of TS mRNA noted in some tumor samples.