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Germline Elongator mutations in Sonic Hedgehog medulloblastoma

Waszak, Sebastian M. and Robinson, Giles W. and Gudenas, Brian L. and Smith, Kyle S. and Forget, Antoine and Kojic, Marija and Garcia-Lopez, Jesus and Hadley, Jennifer and Hamilton, Kayla V. and Indersie, Emilie and Buchhalter, Ivo and Kerssemakers, Jules and Jäger, Natalie and Sharma, Tanvi and Rausch, Tobias and Kool, Marcel and Sturm, Dominik and Jones, David T. W. and Vasilyeva, Aksana and Tatevossian, Ruth G. and Neale, Geoffrey and Lombard, Bérangère and Loew, Damarys and Nakitandwe, Joy and Rusch, Michael and Bowers, Daniel C. and Bendel, Anne and Partap, Sonia and Chintagumpala, Murali and Crawford, John and Gottardo, Nicholas G. and Smith, Amy and Dufour, Christelle and Rutkowski, Stefan and Eggen, Tone and Wesenberg, Finn and Kjaerheim, Kristina and Feychting, Maria and Lannering, Birgitta and Schüz, Joachim and Johansen, Christoffer and Andersen, Tina V. and Röösli, Martin and Kuehni, Claudia E. and Grotzer, Michael and Remke, Marc and Puget, Stéphanie and Pajtler, Kristian W. and Milde, Till and Witt, Olaf and Ryzhova, Marina and Korshunov, Andrey and Orr, Brent A. and Ellison, David W. and Brugieres, Laurence and Lichter, Peter and Nichols, Kim E. and Gajjar, Amar and Wainwright, Brandon J. and Ayrault, Olivier and Korbel, Jan O. and Northcott, Paul A. and Pfister, Stefan M.. (2020) Germline Elongator mutations in Sonic Hedgehog medulloblastoma. Nature, 580 (7803). pp. 396-401.

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Official URL: https://edoc.unibas.ch/76438/

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Abstract

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children; 1,2; , and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma; 3; . Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB; SHH; ); .; ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB; SHH; . Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype; 4; and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U; 34; ) position; 5,6; . Tumours from patients with ELP1-associated MB; SHH; were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems; 7-9; . Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Environmental Exposures and Health > Physical Hazards and Health (Röösli)
UniBasel Contributors:Röösli, Martin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Macmillan
ISSN:0028-0836
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:23 Apr 2020 14:41
Deposited On:23 Apr 2020 14:41

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