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Neuroblastoma: decision on malignancy already made during pregnancy

No. 18 | 27/03/2023 | by Moos

Neuroblastomas, common tumors in infants and young children, develop during the first trimester of pregnancy, regardless of their later clinical course. It is already at this time that it is decided whether they will later regress spontaneously or progress aggressively. This has now been discovered by a team of researchers from the German Cancer Research Center (DKFZ) and the Hopp Children's Cancer Center Heidelberg (KiTZ). Based on the development history of the cancer cells, it is also possible to make predictions about the course of the disease, the study shows using a mathematical model. This should help in the future to make the right therapy decision for affected children.

The Hopp Children's Cancer Center Heidelberg (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and the University of Heidelberg (Uni HD).

In neuroblastomas, cell division gets out of hand: instead of dividing chromosomes (blue) evenly among daughter cells, several spindle poles (green) and spindle apparatuses (red) form, even leading to the breakage of chromosomes or their incorrect division.
© Sina Kreth/KiTZ

Neuroblastomas are among the most common tumors in infants and young children. They occur in the area of the adrenal glands or along the spine in the neck, chest or abdomen. A distinctive feature of neuroblastomas is their extremely variable disease course: In some cases, the tumor regresses completely without any therapy. In about half of the patients, however, even highly intensive therapy cannot prevent aggressive growth.

However, there is currently no internationally recognized uniform method to reliably distinguish high-risk patients from those with a favorable disease course already at initial diagnosis.

"Until now, it was assumed that these were completely different neuroblastoma diseases," says Thomas Höfer of the German Cancer Research Center (DKFZ). The team led by research group leaders Höfer and Frank Westermann from the Hopp Children's Cancer Center Heidelberg (KiTZ) and DKFZ has now been able to show for the first time that both neuroblastomas from high-risk patients and those with a favorable disease course have a common cellular origin. Already in embryonic development during the first third of pregnancy, cell division starts to get out of control and already there the course is set for a favorable or aggressive course in children, the present study shows.

For this purpose, the scientists decoded the tumor genome of 100 patients with neuroblastomas of different stages. They then reconstructed the genesis of the tumors on the basis of specific genetic alterations. "It is assumed that genetic changes in our genome accumulate randomly and over time at a constant rate like sand in an hourglass," explains the study's first author Verena Körber from Thomas Höfer's Theoretical Systems Biology group at DKFZ. "This is also called a molecular clock and can be measured. With the help of a specially developed mathematical model, we were able to reconstruct a family tree of neuroblastoma development from this," Körber continues.

The family tree shows at what point the cancer cells take very different developmental paths and which genetic events are decisive for this. By correlating the results with the clinical course, the scientists were able to divide neuroblastomas into two categories: Those in which genetic alterations lead to tumor growth early on. "Paradoxically, these are the tumors with a favorable course, even if they initially grow faster. But drastic genetic events no longer take place, giving the cancer cells the tools to become immortal in the long term," explains Frank Westermann, an expert in childhood neuroblastoma at KiTZ and DKFZ. "They are also usually detected earlier in children because of their early rapid growth."

The second category is neuroblastomas that become malignant later but then grow aggressively. They undergo a more complex and protracted evolution. Thomas Höfer sees the reasons for this in the fact that, due to the cell environment or internal genetic damage, most of these neuroblastoma cells die: "Due to this selection pressure, however, they then develop particularly aggressive mechanisms to permanently escape cell death and remain infinitely active in division. Until that happens, however, the tumors remain small for the time being and are therefore unfortunately diagnosed later."

Mathematical models of cancer evolution are also currently being researched in adult oncology in order to predict the course of disease in leukemias, for example.
In children with neuroblastoma, they could help distinguish young high-risk patients from children who don't need therapy at all, the research team hopes. "We are currently working to establish tumor evolution as a reliable biomarker in neuroblastoma," Westermann says. "Ideally, such an analysis would then take only about three weeks after sample collection to provide an individualized therapy recommendation."

An image for this press release is available for download at:
https://www.kitz-heidelberg.de/fileadmin/media/kitz/news/2023/230327-mitose_test-KiTZ.jpg 

Caption:
In neuroblastomas, cell division gets out of hand: instead of dividing chromosomes (blue) evenly among daughter cells, several spindle poles (green) and spindle apparatuses (red) form, even leading to the breakage of chromosomes or their incorrect division.

Original publication:
Körber, V. et al. Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome. In: Nature Genetics (Online publication March 27, 2023)
DOI: 10.1038/s41588-023-01332-y

Note on use of images related to press releases
Use is free of charge. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) permits one-time use in the context of reporting about the topic covered in the press release. Images have to be cited as follows: "Source: Sina Kreth/KiTZ".
Distribution of images to third parties is not permitted unless prior consent has been obtained from DKFZ's Press Office (phone: ++49-(0)6221 42 2854, E-mail: presse@dkfz.de). Any commercial use is prohibited.

The Hopp Children's Cancer Center Heidelberg (KiTZ)
The „Hopp Children's Cancer Center Heidelberg" (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital and Heidelberg University. As the National Center for Tumor Diseases (NCT), which focusses on adult oncology, the KiTZ is based on the US model of so-called "Comprehensive Cancer Centers" (CCC). As a therapy and research center for oncologic and hematologic diseases in children and adolescents, the KiTZ is committed to scientifically exploring the biology of childhood cancer and to closely linking promising research approaches with patient care– from diagnosis to treatment and aftercare. Children suffering from cancer, especially those with no established therapy options, are given an individual therapy plan in the KiTZ, which is created by interdisciplinary expert groups in so-called tumor boards. Many young patients can participate in clinical trials which ensures access to new therapy options. Thus, the KiTZ is a pioneering institution for transferring research knowledge from the laboratory to the clinic.
While the KiTZ focuses on pediatric oncology, the focus of the National Center for Tumor Diseases (NCT), founded in 2004, is adult oncology. Both facilities in Heidelberg are based on the US model of so-called "Comprehensive Cancer Centers" (CCC).

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. At DKFZ, more than 1,300 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful.
DKFZ's Cancer Information Service (KID) provides individual answers to all questions about cancer for patients, the general public, and health care professionals.
Jointly with partners from Heidelberg University Hospital, DKFZ runs the National Center for Tumor Diseases (NCT) located in Heidelberg and Dresden, and, also in Heidelberg, the Hopp Children's Cancer Center (KiTZ). In the German Cancer Consortium (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center at the NCT and DKTK sites is an important contribution to the endeavor of translating promising approaches from cancer research into the clinic in order to improve the chances of cancer patients.
DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

Heidelberg University Hospital and Faculty of Medicine: Internationally Renowned Patient Care, Research and Teaching
Heidelberg University Hospital (Universitätsklinikum Heidelberg, UKHD) is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University (Medizinische Fakultät Heidelberg, MFHD) belongs to the internationally renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. Heidelberg University Hospital and the Medical Faculty of Heidelberg University employs around 14.500 employees and is committed to providing trainings and qualifications. Every year, around 86,000 patients and more than 1.100.000 outpatient cases are treated in more than 50 clinical departments with almost 2.500 beds.
Together with the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the German Cancer Aid, the UKHD established the first National Center for Tumor Diseases (NCT) in Heidelberg. The goal is to provide care at the highest level as an oncology center of excellence and to rapidly transfer promising approaches from cancer research to the hospital. In addition, the UKHD operates in partnership with the DKFZ and the University of Heidelberg the Hopp Children's Cancer center Heidelberg (KiTZ), a unique and nationally known therapy and research center for oncological and hematological diseases in children and adolescents.
The Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany. Currently, there are about 4.000 future physicians studying in Heidelberg. www.klinikum.uni-heidelberg.de

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