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29. June 2021
Research team from CEITEC Masaryk University (MU) and from the University Hospital Brno (UHB), led by professor Sarka Pospisilova, clarified the clinical significance of mutations in a key tumour suppressor called TP53, which serves as a central defender of cells against cancer. This breakthrough scientific work was mainly possible thanks to the long-running collaboration between CEITEC researchers and a team of diagnosticians and clinicians from the Department of Internal Haematology and Oncology (UHB) led by Professor Michael Doubek. The research results were published in the scientific journal Blood.
The main authors of this work Jitka Malcikova and Sarka Pavlova have been studying the tumour suppressor called TP53 for many years. This gene is one of the most studied genes, because it is the most frequently mutated gene in human tumours, and at the same time it also serves as a protector of the human genome. In the past, the research team has made a significant contribution to the discovery that mutations in TP53 are associated with resistance to chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). Therefore, patients with a defect in the TP53 gene in leukemic cells are currently indicated for targeted biological drug therapy instead of chemoimmunotherapy.
However, mutations can be present only in a very small proportion of tumour cells below the detection limit of the classical sequencing methods. The researchers from the Centre for Molecular Medicine at CEITEC MU have developed a new method using modern sequencing technology, which allows to detect mutations that are present in less than 1% of the sample with high degree of certainty. Researchers and doctors have used this method to detect small leukemic clones carrying a defect in the TP53 gene. "We have shown that patients with TP53 mutations below the detection limit of classical sequencing, who have been treated with chemoimmunotherapy, have a high risk of mutated cells outgrowing other tumour cells if the disease relapses. This results in a more aggressive course of the disease and significantly shortens the survival of patients, “explains Jitka Malcikova, the first author of the study.
However, when the patients are treated with targeted biological drugs, such as BCR (B-Cell Receptor) inhibitors, this expansion of TP53-mutated tumour clones does not occur. The results indicate that all patients carrying TP53 mutations, regardless of the size of the mutant clone, should be treated with targeted biologic therapy. "This important finding will make it possible to significantly expand the number of patients that can be treated with modern and more effective targeted therapy. The newly described approach to molecular genetic diagnostics of the disease will prevent the development of resistance to chemotherapy, which will significantly prolong the survival and improve the quality of life of many CLL patients,” concludes Professor Sarka Pospisilova, corresponding author of this study.