Rapid screening sorts the cancer drivers from the passengers
2 December 2008
Cancer is often caused by multiple mutations in the genome. But the high levels of DNA damage in many tumours make it difficult to distinguish the ‘driver’ mutations that cause the cancer from those that are side-effects of the disease, known as passenger mutations.
The Sanger Institute’s new method, published in 'Proceedings of the National Academy of Sciences', allows researchers to screen thousands of genes in hundreds of tissues at once and should allow cancer researchers to quickly identify the drivers from the passengers.
“Genome-wide cancer studies are uncovering hundreds of mutations from tens of tissues, but we face a challenge in determining which are driving the development of cancer,” says Dr Pentao Liu, Investigator at the Wellcome Trust Sanger Institute.
“Our system should rapidly take us from many possible mutations to the small number of critical mutations, speeding work to understand the biology of cancer and to define important diagnostic or therapeutic targets.”
The screening system relies on two factors. First, it takes advantage of the way that genes are expressed. Protein-coding genes are controlled by nearby regulatory sequences - known as promoters - that do not themselves code for a protein but control an adjacent gene, switching it on or off, or the level of expression up or down, in the right cells at the right time.
Second is the use of transposons - unusual DNA sequences that can be induced to hop around into multiple new locations in a genome. The system uses these transposons to transport potentially cancer-causing gene segments into new locations in a mouse’s genome.
The system effectively screens billions of cells in just one mouse. If the gene sequence carried by the transposon jumps close to a promoter, it will be controlled by the promoter sequence and expressed. And if that sequence is a cancer-driving mutation it causes a tumour. Thus, researchers can identify which gene sequences are drivers.
The genes studied by the researchers had the potential to cause cancer in different tissues or organs. Many mice developed multiple tumours, including major human types such as carcinomas, sarcomas and hematopoietic malignancies.
The researchers hope their method will add biological understanding to the flow of genomic information from projects such as the Sanger Institute’s Cancer Genome Project and the International Cancer Genome Consortium.
Image: Five mouse nuclei showing chromosomes at the pachytene stage of meiosis; MRC NIMR/Wellcome Images.
References
Qin S et al. A DNA transposon-based approach to validate oncogenic mutations in the mouse. Proc Natl Acad Sci 2008; DOI: 10.1073/pnas.0807785105. [Epub ahead of print]