How metastases grow
What causes the metastasis of malignant tumors in humans?
Weekly "Pharmacy" www.apteka.ua based on Stanford Medicine: Same mutations underpin spread of cancer in individuals
Scientists from the Stanford University School of Medicine, USA, conducted a study based on the data of which they came to understand the key mechanism of the metastasis process in individual patients.
Most cancer-related deaths are caused by metastases or secondary tumors in remote areas of the body that have spread from the original maternal tumor. If primary tumors are often surgically removed, then treatment of metastatic tumors usually requires standard chemotherapy or targeted therapy. The success of these new targeted therapies depends on the presence of a specific mutation in all cancer cells, in particular in metastatic tumors.
Until now, most studies aimed at deciphering the genetic variability or heterogeneity of cancerous tumors have mainly focused on primary tumors. And although this information is still extremely important, it leaves much of the mystery unrecognized, since the cells of malignant tumors are known for their ability to change, accelerated division and evasion of treatment, especially when they spread in the body.
"We took samples from several metastases that had not previously been amenable to therapy from each patient. At the same time, a combination of overlapping genes and various mutation drivers was observed," said Johannes Reiter, lecturer in the Department of Radiology at Stanford University Medical School. "But with the help of computational analyses, we assumed that the drivers of mutations that most likely caused the development of cancer were distributed among all metastases in each patient."
A tumor consisting of billions of cells is riddled with genetic mutations. Cancer and normal cells acquire multiple mutations as they divide. Identification of the drivers of mutations that make a significant contribution to the development of cancer is crucial for immuno-oncology, with which doctors seek to treat a patient's malignant tumor based on its genetic composition.
"Doctors can take a sample of the primary tumor and find some mutation, let's call it mutation "X", in the driver genes and then treat it with a drug that targets this driver gene in order to specifically destroy all cells that have the mutation "X", - says Y.Reuters. – But what if this particular mutation exists only in some of the patient's metastases? Only metastases consisting of cells with the "X" mutation will respond to treatment and stop their growth or die. Cells without the "X" mutation will continue to grow. In the end, the doctor will not see remission of cancer in the patient if the mutation drivers were different in all metastases. That is why it is very important for us to know whether the mutations of the driver gene are the same in all metastases of the patient," the scientist stressed.
What is actually the true driver of the mutation?
Mutation drivers occur in genes involved in the genesis of tumors, such as genes that usually control cell division. When these genes mutate, they can prompt the cell to divide uncontrollably, which leads to the development of cancer. While a huge number of driver genes have been identified for all types of cancer over the past decades, a relatively small number of mutations are considered important in the development of cancer in humans. Similarly, it is difficult to understand which of them are really "guilty", and which are "passenger mutations" or harmless mutations that occur accidentally, "passing through", even if they originated in the driver genes.
To find out whether the driver gene mutations are the same in all cancer metastases, J. Reuter and his colleagues analyzed DNA samples from 76 metastases that had not previously been treated in a group of 20 patients with 8 different types of malignant tumors. At the same time, the scientists were convinced that at least 2 separate metastases were selected from each participant.
During the experiment, the scientists selected mutations that occurred in known driver genes and found out whether they were detected in all metastases taken from individual patients. In some types of malignant tumors, researchers identified only 2 mutations of the driver gene; in others, 18.
Analyzing the results obtained in the context of massive databases containing mutation data of more than 25 thousand previously sequenced genes of various types of cancer, the researchers found that the mutation driver genes, which are distributed among all human metastases, also often mutated in previously sequenced genes of malignant tumors. This indicates that these mutations are the true drivers of the disease and play a crucial role in the development of cancer.
During the experiment, the scientists also managed to determine that several mutation drivers that were not detected in all cancer metastases in the patient, as previously assumed, have weak functional consequences or have no functional consequences. In other words, mutations that were not noted in all metastases were probably "passenger mutations", despite their appearance in the driver genes and probably did not play a decisive role in the development of cancer. According to J. Reuter, this discovery may provide new opportunities for understanding and interpreting tumor biopsies in the future.
Confirming the discovery of common mutation drivers, J. Reuter reported that it is still too early to generalize these data due to the small size of the cohort. But the results of the study do indicate that tumor samples from a single metastasis usually represent a complete set of functional drivers-mutations of a particular patient's cancer. Scientists hope to expand the study to more patients with different types of cancer. "Studies of treated samples cannot provide the same mechanistic understanding of the evolution of cancer, since the observed mutations may be the result of treatment and, perhaps, would not have been observed if another treatment had been chosen or not at all. We want to see if the idea of common functional drivers is supported when working with 20-30 types of malignant tumors and hundreds of untreatable samples," the scientist says.
The results of the study are published in the journal Science (Reiter et al., Minimal functional driver gene heterogeneity among untreated metastases – VM).
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