A new parameter to evaluate the aggressiveness of tumors

(by Manuela Correra) Evaluating the aggressiveness of a tumor and its resistance to therapies to best 'calibrate' the treatments. A goal that we aim to achieve thanks to to the use of a new parameter, developed starting from from observing the speed with which DNA mutates, especially in tumor metastases. The study is signed by researchers from the Candiolo Institute-Ircss and promises to have important repercussions on the lives of patients. For this reason, earned the cover of the journal Science Translational Medicine. The result was achieved under the guidance of Andrea Bertotti and Livio Trusolino, heads of the Laboratory of Translational Oncology and Professors of Histology at the Department of Oncology, University of Turin. I researchers used colon tumor organoids - replications 3D miniatures from patient donor samples - to calculate the DNA mutation rates during the development and progression of cancer, demonstrating that the Tumor DNA mutation rate increases in metastases, with important implications for understanding the mechanisms of neoplastic evolution. The results, the authors say of the study, open new perspectives for applying the calculus of the mutation rate as an evaluation parameter of tumor aggressiveness and resistance to therapies. In the study, explains Trusolino, "we discovered that not only Mutations accumulate at extremely variable rates in tumors of different patients, but they are generated with greater intensity in more advanced lesions, typically metastases." In the work, the researchers analyzed the entire genome of tumor organoids, or 'mini-colons' obtained from samples taken from the patients, at time zero of the beginning of the experiment, and they compared it with that of the same organoids after six months and a year of continuous tumor propagation. "We have subtracted the mutations present at time zero from those present finally to identify those accumulated ex novo, and we have divided their number by the number of cell duplications. In this way, we calculated the mutation rate, which was revealed to be very heterogeneous and systematically higher in the organoids obtained from advanced lesions versus organoids from earlier tumors", explains Elena Grassi, head of the bioinformatics analysis team, which coordinated the studies molecular. A tumor that progresses by adding mutations to increasing speed also has more and more arrows to its bow. "A tumor that mutates more and more acquires new abilities that make you more flexible and resilient to bear insults therapeutic", comments Bertotti. The study has substantial implications: the researchers have observed that new mutations that stratify over time during tumor progression they leave a molecular imprint which can be captured not only in end-stage organoids experiment, but also in diagnostic samples of tumors of patients. "Our next goal is to analyze the pervasiveness of this imprint - concludes Bertotti - to try to date the time when the cancer started. This helps us will allow us to distinguish, given the same age of patients, between tumors onset early and progress slowly compared to tumors which have manifested themselves in more recent times, but have undergone a rapid evolution. The aim is to better understand what the elements that distinguish the most aggressive tumors from the most indolent, with the aim of better focusing on development of new therapeutic approaches". The study was conducted in collaboration with the Institute of Cancer Research in London and research centres in Milan (Ifom, Human Technopole, Niguarda Hospital, National Institute Tumori, European Institute of Oncology) and was funded by the 5x1000 program of Airc and the Piedmontese Foundation for the Cancer Research.