DNA pest
Extra-chromosomal DNA affects the development of the tumor and increases its resistance to treatment
Olga Shutova, PCR.news
Why does the treatment of patients suffering from the same cancer with the same drug sometimes lead to different results? This question was asked by the participants of the PCAWG (Pan-Cancer Analysis of Whole Genomes) project, whose goal is to catalog all biological pathways associated with different types of cancer for the targeted treatment of malignant neoplasms. In particular, it was found that the amplification of oncogenic extra-chromosomal DNA (extrachromosomal DNA, ecDNA) leads to aggressive tumor growth, drug resistance and a reduction in patient survival. However, the inheritance of hcDNA and its functional consequences, the influence of hcDNA on somatic variability and selection have been poorly studied so far.
To understand this, a team of scientists from leading research centers in the United States, Great Britain, Austria and Germany conducted a comprehensive study that used computer modeling and visualization to track the patterns of hcDNA in living cancer cells from commercial cell lines and patient tumor samples.
The authors of the work suggested that during cell division, HCDNAS are unevenly distributed between daughter cells. Using the method of fluorescent in situ hybridization (fluorescence in situ hybridization, FISH), immuno-staining and imaging, researchers quantified the distribution of hcDNA in daughter cells obtained after mitotic division in cell lines of prostate cancer, stomach, colon, neuroblastoma and glioblastoma. It turned out that for these types of cancer, the results coincide with theoretical predictions about random segregation of hcDNA and its impact on the evolution and biology of tumors. These results were also confirmed when imaging live prostate cancer cells containing hcDNA with a fluorescent label.
After seeing significant differences in the daughter cells of the hcDNA, scientists came to the conclusion that extra-chromosomal sequences can contribute to the genetic heterogeneity of tumors. The presence of hcDNA in certain cancer cells helps tumors evade treatment, or rather, adapt to it.
The authors of the work believe that "extra—chromosomal DNA, accelerating the development of tumor cells and increasing their adaptability, uniquely implements each of the fundamental principles of Darwinian evolution - random inheritance by origin, increased variability due to random segregation and selection. Such observations," the researchers write, "may explain why the clinical activity of therapy aimed at oncogenic amplification is limited in tumors such as glioblastoma, where hcDNA is common."
Article by Lange et al. The evolutionary dynamics of extrachromosomal DNA in human cancers is published in the journal Nature Genetics.
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