Colon Cancer: Italian Study Reveals How Its DNA Changes

From today, we can add a new characteristic to the “identity card” of colon tumors: the speed with which they mutate, which varies from case to case and increases in metastases. Information on the evolution of these tumors that will help to further personalize therapies, so much so that the discovery earned the cover of this week's Science Translational Medicine .

An Italian discovery

The result is the fruit of a long and patient Italian work, conducted by the Candiolo Institute - Irccs in collaboration with the Institute of Cancer Research in London and several centers in Milan (Ifom, Human Technopole, Niguarda Hospital, National Cancer Institute, European Institute of Oncology), funded by the 5x1000 program of the Airc Foundation and the Piedmont Foundation for Cancer Research. The study was coordinated by Andrea Bertotti and Livio Trusolino , heads of the Translational Oncology Laboratory of the Irccs of Candiolo and full professors of Histology at the University of Turin.

Colon cancers are not all the same

As has been known for some time, colon cancers are not all the same. In Italy, they affect over 40,000 people every year and 20% are discovered in an advanced stage. In about 5% of cases, a characteristic is present (called microsatellite instability) that generates a high rate of mutations: an index of aggressiveness and resistance to some therapies, but also of a good response to immunotherapy. The new study concerns the remaining 95% of cases.

The study on organoids

The researchers started with “mini-colons” (tumor organoids) obtained from tumor samples taken from the patients themselves, and analyzed their entire genome at the beginning of the experiment, after six months and after a year of continuous growth. “We subtracted the mutations present at time zero from those present at the end to identify those accumulated de novo , and we divided their number by the number of cell duplications. In this way we calculated the mutation rate, which turned out to be highly variable and higher in organoids obtained from advanced lesions (metastases, ed .) compared to organoids derived from earlier tumors,” explains Elena Grassi , researcher at the Department of Oncology, head of the bioinformatics analysis team and first author of the study.

The team focused mainly on cases in which the primary colon tumor and a liver metastasis had been removed at the same time: “The tissues were dissociated into single cells to generate the organoids, which we cultivated continuously for a long time. It was a patient job with many logistical difficulties, especially because the first tests began during the lockdown,” continues Valentina Vurchio , a biotechnologist at the Translational Oncology Laboratory in Candiolo, who conducted the organoid propagation experiments.

Measuring the growth rate of tumors

But the result was worth the long wait: the researchers observed that the new mutations that stratify over time during tumor progression leave a molecular imprint that can also be found in patient tumor samples (and not only in organoids). The next step will therefore be to analyze the presence of this "signature" and use it as a "dating method" for the tumor: "This will allow us to distinguish tumors that arose early and progressed slowly from tumors that appeared more recently but have evolved rapidly," concludes Bertotti. "The goal is to better understand what elements distinguish the most aggressive tumors from the most indolent ones, with the aim of better focusing the development of new therapeutic approaches."