The causes of 40 percent of all cases of certain medulloblastoma - dangerous brain tumors affecting children - are hereditary. These are the findings of a recent genetic analysis carried out by scientists from the Hopp Children's Cancer Center (KiTZ), the European Molecular Biology Laboratory (EMBL) and numerous colleagues around the world, which have just been published in the scientific journal Nature. A genetic defect that occurs in 15 percent of these children plays a key role by destabilizing the production and breakdown of proteins. The researchers suspect that protein metabolism defects could be a previously underestimated cause of other types of cancer.
The "Hopp Children's Cancer Center Heidelberg" (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and Heidelberg University.
Medulloblastoma are among the most common malignant brain tumors affecting children. They spread from the cerebellum to the surrounding tissue and can also spread to other parts of the central nervous system via the cerebrospinal fluid. Because these tumors grow rapidly, physicians do not have much time to find a suitable treatment.
Physicians at the Hopp Children's Cancer Center (KiTZ) specialize in characterizing the molecular properties of children's cancers in order to be able to recommend other treatment options besides standard therapies, and to develop new therapies with a focus on the mode of action.
Together with colleagues from EMBL, the German Cancer Consortium (DKTK) and the St. Jude Children's Research Hospital in Memphis, USA, the KiTZ researchers conducted the most comprehensive medulloblastoma-related genetic investigation to date. They analyzed the genome and tumor genome of 800 children, young people and adults with medulloblastoma and compared the genetic data with data from healthy individuals. In doing so, they came across a particularly striking hereditary difference in children and young people with brain tumors in the Sonic Hedgehog medulloblastoma subgroup.
A hereditary genetic defect in 15 percent of cases meant that patients were no longer able to produce the elongator complex protein 1 (ELP1) in the tumor. The elongator complex protein is involved in ensuring that proteins are properly assembled and folded in line with the genetic code. The latest findings show that, without ELP1, much of the protein metabolism is disturbed: "The assembly and folding of larger proteins in particular does not function properly any more, and the accumulation of these non-functioning or malfunctioning proteins places the cells under permanent stress," says KiTZ Director Stefan Pfister, who is a head of department at the DKFZ and an expert in targeted therapies within the DKTK. "Hundreds of proteins are misregulated in this way, including proteins that are important for nerve cell development."
By analyzing the genome of some parents and grandparents, the researchers also established that the cancer-activating ELP1 genetic defect is hereditary. "That makes this the most common congenital genetic defect associated with medulloblastoma to date", says Jan Korbel, a co-author of the study who works at EMBL. Lead author Sebastian Waszak adds: "The latest results show that around 40 percent of children and young people who suffer from this subtype of medulloblastoma have a congenital genetic predisposition for it. That is a much higher proportion than we had assumed." Identifying hereditary causes of cancer in advance can help to make the right therapeutic decision and reduce the risk of relapse in children. "For example, in the case of a hereditary predisposition for DNA breaks, certain chemotherapies or radiotherapy can lead to secondary tumors. In such cases, the first disease should not be treated too aggressively," says Stefan Pfister.
S. Waszak, G. Robinson, et al. Germline elongator mutations in sonic hedgehog medulloblastoma. In: Nature (Online Publication 1st April 2020). DOI: 10.1038/s41586-020-2164-5
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Without the ELP1 assembly and folding of proteins does not function properly any more.
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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 Medical Faculty
Internationally recognized patient care, research, and teaching Heidelberg University Hospital is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University belongs to the internationally most renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. With about 13,000 employees, training and qualification is an important issue. Every year, around 65,000 patients are treated on an inpatient basis, 56,000 cases on a day patient basis and more than 1,000,000 cases on an outpatient basis in more than 50 clinics and departments with almost 2,000 beds. Jointly with the German Cancer Research Center (DKFZ) and German Cancer Aid, Heidelberg University Hospital has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. Currently, about 3,700 future physicians are studying in Heidelberg; the reform Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany. http://www.
European Molecular Biology Laboratory
EMBL is Europe's flagship laboratory for the life sciences. Established in 1974 as an intergovernmental organisation, EMBL is supported by over 20 member states. EMBL performs fundamental research in molecular biology, studying the story of life. The institute offers services to the scientific community; trains the next generation of scientists and strives to integrate the life sciences across Europe. EMBL is international, innovative and interdisciplinary. Its more than 1600 staff, from over 80 countries, operate across six sites in Barcelona (Spain), Grenoble (France), Hamburg (Germany), Heidelberg (Germany), Hinxton (UK) and Rome (Italy). EMBL scientists work in independent groups and conduct research and offer services in all areas of molecular biology. EMBL research drives the development of new technology and methods in the life sciences. The institute works to transfer this knowledge for the benefit of society.