Cancer is caused by faults in the DNA, the hereditary information in your cells. By studying all the genes in a tumor, researchers can better understand how the tumor developed and find genetic weaknesses that can be targeted with precision drugs.
Scientists at the Princess Máxima Center analyzed the DNA of more than 2,500 tumors of children with cancer. Using computer statistical analyses, they looked at 23 different types of childhood cancer. The results were published this week in the journal Communications Biology. The study was funded by KWF and the Maarten van der Weijden Foundation.
The researchers were not looking for individual abnormalities in the DNA of the tumors, but rather for combinations of DNA changes that are found in the same tumor often, or never. The team discovered 15 gene pairs that frequently occurred together.
In some cases, the gene pairs are no more than a hallmark of a specific form of childhood cancer. But sometimes combinations indicate an interaction between the genes. ‘DNA abnormalities that we often see together can be important for the tumor,’ dr. Patrick Kemmeren, who led the study, explains. ‘Such gene pairs can help a tumor develop or grow, for example.’
The team also found 27 combinations of genes that almost never occur in the same tumor. These pairs teach scientists something different. Kemmeren: ‘The two genetic abnormalities together can be ‘synthetic lethal’. This means that the tumor can survive if it has one of the two DNA abnormalities, but not if both genes have a fault.’ The researchers believe this could be the case with three interactions that they discovered in the new study.
Synthetic lethal gene pairs offer perspective for new treatments. If a drug blocks the second gene in the combination, the cancer cell will die. Such a drug then works specifically on the tumor cells, leaving healthy cells alone.
It is still too early for that, says Kemmeren, but this study is an important first step. ‘We’ve not only mapped genetic interactions in childhood cancer, but we are also starting to study the combinations to understand how the interactions work, and why the interactions are important for the tumor cells.’
The researchers are already studying one pair of DNA abnormalities in more detail, working with the Drost group. Abnormalities in the two genes, Drosha and P53, are found in Wilms’ tumor, a form of kidney cancer in children, but almost never in combination. Kemmeren: ‘In 3D mini kidney tumors in the lab we are now investigating whether the growth of the tumor cells is slowed down if we block the Drosha gene. We’re also trying to better understand how the interaction between the Drosha and P53 gene works.’
‘Our research group at Máxima is one of few in the world that are seriously looking at genetic interactions in childhood cancer,’ says Kemmeren. ‘An enormous amount of data is needed to properly map out genetic interactions.’
For this study, the researchers used DNA data from tumors from children treated at the Deutsches Krebsforschungszentrum in Heidelberg, Germany, and St Jude's Children's Hospital in the United States. The team is also working on a pipeline to analyze the entire DNA of children whose tumor tissue is stored in the Biobank of the Princess Máxima Center.