The research group of Hugo Snippert, Oncode Investigator at the Center of Molecular Medicine at UMC Utrecht, reports the first detailed insights into the pace and patterns by which genetic alterations are generated by tumours.
A technical breakthrough allows the researchers to combine microscopic ‘live’ recordings of cell divisions with genetic characterisation of those same individual tumour cells. The results appeared in the journal Nature Genetics and shed new light on the origin of colon tumours. This knowledge may help predict whether benign colon polyps can eventually transform into malignant cancers.
Colorectal cancer is a disease that kills nearly 5000 people in the Netherlands each year. Although there are indications that genetic variation in these tumours is related to the severity of the disease, it was still unclear how and at what rate this variation arises.
"Until now, we were not able to independently analyse the two most important variables that drive the evolution of tumours," said research leader Hugo Snippert. "The final genetic profile of a tumour is the outcome of how often genetic alterations occur and what effect these invoke on the fitness of a tumour cell." The effect on fitness, also known as selection, can be both positive and negative for a tumour cell. For instance, an alteration that makes cancer cells divide faster always outcompetes cells that divide slower or even die because of the alteration.
"We were already capable to map the genetic outcome of that process to great extent, but how both intertwined processes independently impact the course of tumour evolution was a black box until now. For example, we had no idea of the extent of genetic variation that occurs but ultimately does not survive."
In the study, the researchers take a major step toward understanding this process. "In our study, we used cultured mini-tumours, called organoids," explained Yannik Bollen, one of the two principal researchers in this study. "In those mini-tumours, we can make microscopic recordings of all cell divisions and then reconstruct the genetic alterations per newly formed cell." The result is a very precise overview of how and when genetic changes occur in a tumour. "It has been assumed for a long time that genetic abnormalities in tumours accumulate in a slow, gradual manner, but we often see multiple large alterations occurring in just a single cell division."
Ellen Stelloo, the other principal researcher, outlined the spectacular impact of their work: "Mapping the intermediate genomes of an evolving tumour cell greatly enhances our understanding of the disease process of colon cancer. You can compare it to the impact that the discovery of transitional fossils like the Archaeopteryx, a feather-clad dinosaur and widely considered to be the 'first bird', have on our understanding of evolution."
Read the article in Nature Genetics.