“Understanding Genetic Processes of Cancer Metastasis: Findings from UMC Utrecht, Hartwig Medical Foundation, and Vall d’Hebron”

In cancer, a cell gradually changes from benign to malignant because the DNA adapts

Why does one tumor metastasize, and the other does not? Researchers from UMC Utrecht, Hartwig Medical Foundation and Vall d’Hebron are trying to find the answer to that question. Their findings provide very valuable clues for the treatment and prevention of cancer. The results of their two studies have now been published in the leading scientific journals ‘Nature’ and ‘Nature Genetics’.

In cancer, a cell gradually changes from benign to malignant because the DNA adapts. Sometimes it stops there, and we speak of ‘primary cancer’. In some cases, DNA errors accumulate, cells separate from a primary tumor, and the cancer spreads to other parts of the body. This significantly increases the patient’s chance of dying from cancer.

Understanding biological processes
To understand which underlying biological processes play a role in whether or not life-threatening cancer metastases develop, the researchers from UMC Utrecht (Center for Molecular Medicine), Hartwig Medical Foundation in Hebron Valley joined forces for a large-scale investigation. With the help of a unique Dutch data collection, they have been able to analyze the DNA data of more than 7,000 cancer patients.

DNA under scrutiny
In this way, they have now systematically mapped out the differences in genetic properties between primary and metastatic tumors for the 23 most common tumor types. And, very important: they also listed how the tumors bypass the controlling effect of the immune system. The researchers used whole genome sequencing for this large-scale data analysis. With this advanced technique, the complete DNA of tumors is read and it is possible to determine which changes have occurred during and after the development of the tumors.

Metastatic tumor different?
In the first study (featured in Nature) the following question is central: to what extent are metastatic tumors different from primary cancer? To this end, the researchers examined the overall DNA differences between primary and metastatic tumours. Their conclusion: the extent to which the metastatic tumor has changed depends strongly on the type of cancer.

In metastatic skin cancer, for example, there is usually little difference with the primary tumour. But in other cancers, such as metastatic lung and prostate cancer, a lot has changed. So much so that the tumors seem almost unrelated. How is that possible? The extent to which DNA errors accumulate appears to be strongly dependent on a diversity of processes that partly overlap for certain types of cancer, but can also differ greatly, the researchers say. In line with this, they have also found, paradoxically, that previous cancer treatments can help DNA to adapt. In metastatic tumors, for example, new cancer properties were found that had arisen after the development of resistance to previous treatments.

Fooled immune system?
The second study (published in Nature Genetics) focuses on the question: what genetic mechanisms does a cancer cell use to escape our immune system? DNA changes make each tumor cell ‘foreign’. Normally, our immune system recognizes such a foreign cell at an early stage and clears it immediately. But a tumor that has developed further has apparently acquired properties to evade our immune system. This can be done by disruption at the genetic level of various mechanisms in the tumor cell, according to the researchers.

But which genetic trick is used and to what extent by the tumor depends strongly on the type of cancer. The researchers have succeeded in listing exactly how often which mechanisms are activated by which tumor types to disrupt the immune system. This is extremely useful because it allows us to improve the effectiveness of promising immunotherapy treatments, for example.

Personalize and prevent more
The results of the two studies provide a better insight into what happens genetically when tumors metastasize. And they show how our immune system is tricked when and how. The researchers therefore make an important contribution to the possibilities for further personalization of cancer treatments and lay a foundation for developing treatment strategies to prevent the spread of the tumour.

The impact of the studies is likely to be all the greater because all results will be included in datasets that will be made available to cancer researchers and clinicians worldwide.

Research leader and professor of medical genetics Edwin Cuppen (UMC Utrecht and Hartwig Medical Foundation): “The new insights from these studies form a valuable basis for improving diagnosis in cancer patients, personalizing therapeutic treatments and, in the more distant future, , even the prevention of metastatic cancer. The results of the study make it clear how important the systematic collection and disclosure of data for reuse is in the healthcare domain. Without the cooperation and consent of patients, as well as national-scale collaboration with hospitals, this study would have been impossible. And these new valuable insights for improving future oncological care would not have been possible.”

This research was carried out in the context of the Oncode Institutea partnership made possible by KWF Cancer Control and ministries of VWS, OCW in NO.

Bron: Utrecht UMC

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