Medulloblastomas are among the most common malignant brain tumours 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 tumours grow rapidly, physicians do not have much time to find a suitable treatment.
Researchers from European Molecular Biology Laboratory (EMBL), together with colleagues from Hopp Children’s Cancer Center Heidelberg (KiTZ), the German Cancer Consortium, and St. Jude Children’s Research Hospital have conducted the most comprehensive medulloblastoma-related genetic investigation to date.
“We analysed the genome and tumour genome of 800 children, adolescents, and adults with medulloblastoma and compared the genetic data with data from healthy individuals,” explains lead author Dr. Sebastian Waszak from EMBL, who was also part of the EMBL led Pan-Cancer project.
In characterising the molecular properties of medulloblastoma, the scientists hope to be able to recommend other treatment options besides standard therapies, and to develop new therapies with a focus on the mode of action. In analysing the healthy and mutated genome, they came across a particularly striking hereditary difference in children and young people with brain tumours in the so-called Sonic Hedgehog medulloblastoma subgroup.
A hereditary genetic defect in 15 percent of cases meant that tumours were no longer able to produce the elongator complex protein 1 (ELP1). This protein is involved in ensuring that other proteins are properly assembled and folded in line with the genetic code. The latest findings show that, without ELP1, much of the protein production in tumours 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 Dr. Stefan Pfister. “Hundreds of proteins are misregulated in this way, including proteins that are important for nerve cell development.”
By analysing the genomes of some of the parents and grandparents of study participants, the researchers also established that this novel genetic disease is hereditary. “That makes this the most common congenital genetic defect associated with medulloblastoma to date,” says Dr. Jan Korbel, a co-author of the study and group leader at EMBL Heidelberg. Sebastian Waszak, now a group leader at the Norwegian node of the Nordic EMBL Partnership for Molecular Medicine, 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 can 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 tumours. In such cases, the first disease should not be treated too aggressively,” says Stefan Pfister.
Paper: Sebastian M. Waszak, Giles W, Robinson, Brian L. Gudenas, Kyle S. Smith, Antoine Forget, Marija Kojic, Jesus Garcia-Lopez, Jennifer Hadley, Kayla V. Hamilton, Emilie Indersie, Ivo Buchhalter, Jules Kerssemakers, Natalie Jäger, Tanvi Sharma, Tobias Rausch, Marcel Kool, Dominik Sturm, David T. W. Jones, Aksana Vasilyeva, Ruth G. Tatevossian, Geoffrey Neale, Bérangère Lombard, Damarys Loew, Joy Nakitandwe, Michael Rusch, Daniel C. Bowers, Anne Bendel, Sonia Partap, Murali Chintagumpala, John Crawford, Nicholas G. Gottardo, Amy Smith, Christelle Dufour, Stefan Rutkowski, Tone Eggen, Finn Wesenberg, Kristina Kjaerheim, Maria Feychting, Birgitta Lannering, Joachim Schüz, Christoffer Johansen, Tina V. Andersen, Martin Röösli, Claudia E. Kuehni, Michael Grotzer, Marc Remke, Stéphanie Puget, Kristian W. Pajtler, Till Milde, Olaf Witt, Marina Ryzhova, Andrey Korshunov, Brent A. Orr, David W. Ellison, Laurence Brugieres, Peter Lichter, Kim E. Nichols, Amar Gajjar, Brandon J. Wainwright, Olivier Ayrault, Jan O. Korbel, Paul A. Northcott, Stefan M. Pfister. Germline Elongator mutations in Sonic Hedgehog medulloblastoma. Nature, 2020; DOI: 10.1038/s41586-020-2164-5