The research group of Hugo Snippert, Oncode Investigator at the Center of Molecular Medicine at UMC Utrecht, report the first detailed insights into the pace and patterns by which genetic alterations are generated by tumors. A technical breakthrough allows the researchers to combine microscopic ‘live’ recordings of cell divisions with genetic characterization of those same individual tumor cells. The results appeared in the leading journal Nature Genetics and shed new light on the origin of colon tumors. This knowledge may help predict whether benign colon polyps can eventually transform into malignant cancers.

Colorectal cancer is a disease that kills nearly 5,000 people in the Netherlands each year. Although there are indications that genetic variation in these tumors 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 analyze the two most important variables that drive the evolution of tumors," says research leader Hugo Snippert. "The final genetic profile of a tumor is the outcome of how often genetic alterations occur and what effect these invoke on the fitness of a tumor cell." The effect on fitness, also known as selection, can be both positive and negative for a tumor 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 tumor 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."

The archaeopteryx of cancer research
In a new study published in Nature Genetics, the researchers take a major step toward understanding this process. "In our study, we used cultured mini-tumors, called organoids," explains Yannik Bollen, one of the two principal researchers in this study. "In those mini-tumors, 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 tumor. "It has been assumed for a long time that genetic abnormalities in tumors accumulate in a slow, gradual manner, but we often see multiple large alterations occuring in just a single cell division." Ellen Stelloo, the other principal researcher, outlines the spectacular impact of their work: "Mapping the intermediate genomes of an evolving tumor 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."

By leaps and bounds
Intriguingly, the process of genetic instability in cancer cells appears not to be strictly proceeding in a step-by-step manner, but can occur with sudden, singular big jumps. "There were already indications for this in the literature. But how do you demonstrate something has never been there when you simply can't find it? We now address that question by providing direct evidence that tumor cells can skip a lot of genetic intermediates with one cell division", Hugo says. Now that this study has mapped the rate and patterns of genetic alterations, the team wants to focus on selection. In a follow-up study, they will explore whether it is essential for tumor development to make big jumps, or whether it could also have occurred more gradually. For the research Hugo Snippert's group collaborated with a national and international team of colleagues, including Oncode Investigators Edwin Cuppen, Susanne Lens (both UMC Utrecht) and Geert Kops (Hubrecht Institute).

About Oncode Institute
Oncode Institute unites more than 800 excellent fundamental cancer researchers in the Netherlands. Our mission is to foster innovations in the diagnosis and treatment of cancer. The goal is to help patients survive, improve the quality of life for those affected and contribute to a more affordable healthcare system. Oncode Institute translates fundamental insights into the biology of cancer into new diagnostics, new drugs, and innovative treatments. Oncode's three strategic pillars to improve patient outcomes are Excellence in Science, Collaboration and Valorization. Oncode is funded by KWF, together with the Ministries of Economic Affairs & Climate, Education, Culture & Science and Health, Welfare & Sport and Health~Holland, with a total amount of €120 million until 2022. 

Photo: Microscopic image of cell nuclei in an organoid. The yellow cell nucleus (frame 1) contains an extra copy of chromosome 7. In a subsequent cell division, this change takes place again, and the yellow marked daughter cell ends up with 4 copies of chromosome 7 (frame 8).