The causes of 40 percent of all medulloblastoma cases-extreme head tumors affecting children-are hereditary. These are the results of a recent genetic analysis conducted by researchers from the Hopp Children's Cancer Center (Kitz), the European Molecular Biology Laboratory (EMBL), and various colleagues around the world. A genetic disorder found in 15 percent of these kids plays a key role in destabilizing protein development and breakdown. The researchers believe that defects in the protein metabolism may be a previously undervalued cause of other cancer types. The Hopp Children's Cancer Center Heidelberg (Kitz) is a joint organization of the German Cancer Research Center (DKFZ), the University Hospital of Heidelberg (UKHD), and the University of Heidelberg. Medulloblastoma is one of the most common malignant brain tumors that affect children. They spread from the cerebellum to the surrounding tissue, and can also spread through the cerebrospinal fluid to other parts of the central nervous system. Because these tumors are growing rapidly, doctors don't have much time to find proper treatment. Doctors at the Hopp Children's Cancer Center (Kitz) are specialized in identifying the molecular characteristics of child cancers in order to be able to recommend other treatment options in addition to standard medicines and develop new therapies with a focus on the mode of action. Together with EMBL colleagues, the German Cancer Consortium (DKTK), and the St. Jude Children's Research Hospital in Memphis, USA, the Kitz researchers have conducted the most comprehensive genetic investigation on medulloblastoma to date. They analyzed the genome and tumor genome of medulloblastoma in 800 children, young people, and adults and compared the genetic data with data from healthy individuals. In doing so they encountered a particularly striking hereditary difference in the Sonic Hedgehog medulloblastoma subgroup among children and young people with brain tumors. In 15 percent of cases, a hereditary genetic defect meant that patients could no longer produce the elongator complex protein 1 (ELP1) in the tumor. The elongator complex protein is involved in ensuring proper assembly and folding of proteins according to the genetic code. The most recent findings show that much of the protein metabolism is disturbed without ELP1."In particular, the assembly and folding of larger proteins no longer function properly and the accumulation of these non-functioning or malfunctioning proteins puts irreversible stress on the cells," says Kitz Director Stefan Pfister, who is ahead of the DKFZ department and a specialist in targeted therapies within the DKTK."Hundreds of proteins are misregulated in this way, including proteins that are essential for the development of nerve cells." By studying the genome of some parents and grandparents, the researchers have found that the genetic defect ELP1 that causes cancer is inherited. That makes this the most common congenital genetic defect to date associated with medulloblastoma, "says Jan Korbel, a study co-author working at EMBL.

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