May 19, 2023 – 8:35 AM
Large-scale Dutch DNA data analysis shows important and new insights into differences between primary and metastatic cancer. These insights provide relevant starting points for improving cancer treatment. The results of this research have been published today in the renowned journals Nature and Nature Genetics.
Cancer is caused by DNA changes that cause a cell to gradually change from benign to malignant. This can lead to metastases to other parts of the body. By analyzing the DNA data of more than 7,000 patients, the researchers show that there are major differences between primary and metastatic cancer and that there are also tumor types in which the primary tumor and the metastasis hardly differ from each other! By studying the type of DNA change and the consequences of the changes, important insights into the underlying biological processes have been obtained.
Research with complete DNA information of tumors
Researchers from UMC Utrecht, Vall d’Hebron in Barcelona and Hartwig Medical Foundation in Amsterdam and Australia have mapped the DNA changes of the 23 most common tumor types. They have studied the differences in genetic characteristics between the source of the cancer, the primary tumor, and metastatic tumors.
Unique collections of whole genome sequencing data from tumors were used. This enabled the researchers to study in great detail which changes in the tumor had occurred during and after the tumor had developed. The researchers have harmonized and systematically compared the world’s largest publicly available data sets of primary tumors (from the international PCAWG consortium with information from ˜2,800 patients) and metastatic tumors (Hartwig Medical Database, ˜4,400 patients).
Difference between primary cancer and metastatic tumors
The main research question was: ‘To what extent are metastatic tumors different from primary cancers?’ The summary answer is: ‘It depends on the type of cancer’. There are tumor types in which there are no significant changes between the primary tumor and the metastasis, such as skin cancer. In other tumor types, such as lung and prostate cancer, many changes are present and the metastatic tumors could actually be seen as completely different tumors than the original diagnosed cancer.
When asked what exactly is different and what processes underlie this, the answer was the same: ‘That also depends on the tumor type’. By looking at the details of the DNA changes, it was often possible to deduce which biological mechanisms were active and at what stage of tumor development these processes took place. In the advanced development of tumors, other processes often appeared to be active than in the development of tumors. Some of the processes found play a universal role in all cancers, but other processes were very specifically present in a few tumor types. Paradoxically, some previously given anti-cancer treatments turned out to lead to many new DNA changes. New features of the cancer could also be found in metastatic tumors that were the result of resistance to previous treatments.
How does a cancer cell escape the immune system?
In the second publication, the researchers took a closer look at the genetic mechanisms that a cancer cell uses to escape the immune system. Due to the DNA changes that have caused the tumor, each tumor cell becomes a little foreign to the body. This is usually a signal for our immune system, also known as the immune system, to recognize and clear tumor cells at an early stage. Thus, a fully developed tumor must have acquired properties to escape this mechanism.
From a genetic perspective, there are several escape routes for this. For the first time, the researchers systematically investigated which pathways are used in different types of cancer and looked at any differences between primary and metastatic tumours. There are roughly six different escape routes that can be distinguished genetically. There are major differences per cancer type in the presence of one of these escape routes, but there appear to be few differences between primary and metastatic tumours. Escaping the immune system is therefore a property acquired early in tumor development. There are also major differences between cancer types with regard to the mechanism used. Some have a diversity of escape mechanisms, while in others only one or a few are found.
Because a well-functioning immune system is essential for the functioning of promising immunotherapy treatment of cancer, the results of this study are relevant for improving therapy choices and preventing overtreatment.
Research leader Prof. Dr. Edwin Cuppen: ‘The new insights from these studies form a valuable basis for improving diagnostics in cancer patients, personalizing therapeutic treatment and possibly preventing (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 the improvement of future oncological care would not have been possible.’
This research was carried out within the framework of the Oncode Institute, a collaboration made possible by the Dutch Cancer Society and the Ministries of VWS, OCW and EZ. The Hartwig Medical Database is a unique research resource worldwide and was set up by the Hartwig Medical Foundation, a non-profit organization that collaborates with the Center for Personalized Cancer Treatment and a large number of Dutch hospitals to improve diagnosis and care of cancer patients.
Source: Hartwig Medical Foundation