Understanding molecular changes in colorectal cancer is important if new biomarkers and treatment targets are to be defined.
Using oligonucleotide microarrays, researchers from Aarhus University Hospital, Denmark, and the University of Helsinki, Finland, have monitored the gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each pool) of total RNA from left-sided sporadic colorectal carcinomas.
Dr Karin Birkenkamp-Demtroder and colleagues compared normal tissue to carcinoma tissue from Dukes' stages A to D (noninvasive to distant metastasis) and identified 908 known genes that showed alterations from normal to tumor tissue.
An additional 4,155 ESTs showing similar changes were also identified.
Using intensive filtering processes, these numbers were reduced to 226 genes and 157 ESTs that were highly relevant to colorectal cancer.
In greater than 70% of cases the alteration of known genes was confirmed by array analysis of 25 single samples.
By adopting the technique of two-way hierarchical average linkage cluster analysis, the research group found normal tissue to be clustered with Dukes' A, while Dukes' B and Dukes' C clustered together and Dukes' D clustered separately.
|226 genes relevant to colorectal cancer were identified |
| Cancer Research|
Real time PCR of 10 known genes and 5 ESTs demonstrated excellent reproducibility of the array-based findings.
The most frequently altered genes belonged to functional categories of metabolism (22%), transcription and translation (11%), and cellular processes (9%).
15 nuclear encoded mitochondrial proteins were all down-regulated in colorectal cancer.
Several chromosomal locations with clusters of either potential oncogenes or potential tumor suppressors were also identified.
Some of these, commented Dr Birkenkamp-Demtroder, such as aminopeptidase N/CD13 and sigma B3 protein on chromosome 15q25, coincided with a high frequency of loss of heterozygosity.
Looking to the future, she said, "The genes and ESTs presented in this study encode new potential tumor markers as well as potential novel therapeutic targets for prevention or therapy of colorectal cancer."