Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

DOI
Publisher DOI
PubMed ID
32296180
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 children1,2, 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 medulloblastoma3. 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 (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 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 (U34) position5,6. Tumours from patients with ELP1-associated MBSHH 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 systems7-9. 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.
Date Issued
2020-04
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
Waszak, Sebastian M
Robinson, Giles W
Gudenas, Brian L
Smith, Kyle S
Forget, Antoine
Kojic, Marija
Garcia-Lopez, Jesus
Hadley, Jennifer
Hamilton, Kayla V
Indersie, Emilie
Buchhalter, Ivo
Kerssemakers, Jules
Jäger, Natalie
Sharma, Tanvi
Rausch, Tobias
Kool, Marcel
Sturm, Dominik
Jones, David T W
Vasilyeva, Aksana
Tatevossian, Ruth G
Neale, Geoffrey
Lombard, Bérangère
Loew, Damarys
Nakitandwe, Joy
Rusch, Michael
Bowers, Daniel C
Bendel, Anne
Partap, Sonia
Chintagumpala, Murali
Crawford, John
Gottardo, Nicholas G
Smith, Amy
Dufour, Christelle
Rutkowski, Stefan
Eggen, Tone
Wesenberg, Finn
Kjaerheim, Kristina
Feychting, Maria
Lannering, Birgitta
Schüz, Joachim
Johansen, Christoffer
Andersen, Tina V
Röösli, Martin
Grotzer, Michael
Remke, Marc
Puget, Stéphanie
Pajtler, Kristian W
Milde, Till
Witt, Olaf
Ryzhova, Marina
Korshunov, Andrey
Orr, Brent A
Ellison, David W
Brugieres, Laurence
Lichter, Peter
Nichols, Kim E
Gajjar, Amar
Wainwright, Brandon J
Ayrault, Olivier
Korbel, Jan O
Northcott, Paul A
Pfister, Stefan M
Additional Credits
Journal
Nature
Publisher
Macmillan Journals Ltd.
ISSN
0028-0836
Access(Rights)
restricted
Show full item