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The effect of chemotherapy to the genome of cancer cells 6th October 2016


The young researchers of MTA and ELTE both participated in the international cancer-research cooperation, which results were published both in the Genome Biology and the Nature Oncogene journal -can be read on the website of MTA.

The emergence of cancer tumours can basically be explained by one change in the genome of the cell which founds the tumour. Characteristically more than one genome mutation needs to occur for the kick off of the unlimited cell proliferation.

During the copying of the DNA, errors occur continuously, but the stability of the genome of the cells is secured by several DNA-fixing mechanisms. In according to the mutatorhypothesis, the error of the DNA-correction destabilizes the genome, and as a result of this, further gene mutations can occur (oncogenic) in a given cell, which enhance the further cancer processes. The theory backs it up, that the DNA-correction genes’ inheritable errors are susceptive for the formation of tumours, for example the inheritable mutations in the BRCA1 or BRCA2 genes increase the chances of the occurrence of breast-ovary cancer.

The “Lendület” research team of Dávid Szüts (Enzymology Institute of the Natural Sciences Research Center of the Hungarian Scientific Academy), together with the participation of British and American clinicians modelled the processes causing mutations (mutagenetic) in gene-knock out cell lines. For this it was necessary to identify the entire genome of the cells, as well as the exact identification of all the occurring mutations. For the analysis of the bioinformatical data, a very tight cooperation was formed between the researchers of the MTA TTK and the ELTE Complex Systems Physics Department.

For this purpose, Orsolya Pipek PhD- and Dezső Ribli MSc-students developed a new method, which is able to identify genome mutations faster and more punctual than any other system before. The experimental work was led by Bernadett Szikriszt and Judit Zámborszky, the young post-doctoral researchers of the MTA TTK.

According to the results, in the BRCA cells with gene defect; the process of mutation creation really becomes much faster. Although the protein, coded by the BRCA genes has an already known role in the preparation of DNA-breakages, surprisingly not only the deletions indicating the wrong correction of breakages got more concentrated, but the number of the ordinary basis changes increased in a significantly larger ratio. The results published in the Oncogene journal indicate, that the basis changes, to which similar ones were discovered in the genome of tumours, play an important role in the ontogenetic effect of the BRCA gene errors.

The developed experimental system made it possible to model the effects of the chemotherapy treatments in the genome of tumour cells. One of the basic effect-mechanisms of chemotherapies is the demolition of the tumour cells by damaging the DNA. But certain cells often survive the therapy, and in such cells the DNA damaging treatment can cause gene mutations. The researchers examined the effect of several, widely used cytotoxic agents on the genomes of cells that survived the therapy. According to the results published in the Biology journal; among the agents there are some with significant mutagenetic effect, and cause a typical type of gene mutations.

In several clinical cases, the same mutations caused resistance in the BRCA mutant tumours which recurred after the treatment. Based on the above mentioned, the results draft a new mechanism in the evolution of tumours, according to which, the mutagenic chemotherapy enhances the evolving of the resistance against therapy.

Dávid Szüts spoke about his new results in details in the program titled Szigma at InfoRádió.

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