Mbcl-21. Germline Elongator Mutations in Sonic Hedgehog Medulloblastoma
Year: 2020
Type: article
Study design: Observational Study
Abstract: BACKGROUND Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variants in ~5% of all patients. Here, we extended our analysis to include all protein-coding genes. METHODS Case-control analysis performed on 795 MB patients against >118,000 cancer-free children and adults was performed to identify an association between rare germline variants and MB. RESULTS Germline loss-of-function variants of Elongator Complex Protein 1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH). ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH cases and were restricted to the SHHα subtype. ELP1-associated-MBs demonstrated biallelic inactivation of ELP1 due to somatic chromosome 9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32) alterations. Inheritance was verified by parent-offspring sequencing (n=3) and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%; p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a subunit of the Elongator complex, that promotes efficient translational elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associated-MBs exhibit destabilization of the core Elongator complex, loss of tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response. CONCLUSIONS We identified ELP1 as the most common MB predisposition gene, increasing the total genetic predisposition for pediatric MBSHH to 40%. These results mark MBSHH as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.
Source: Neuro-Oncology
Authors: Giles W Robinson, Sebastian M Waszak, Brian L Gudenas, Kyle S Smith, Antoine Forget, Marija Kojic, Garcia-Lopez Jesus, Jennifer Hadley, Kayla V Hamilton, Emilie Indersie, Ivo Buchhalter, Natalie Jager, Tanvi Sharma, Tobias Rausch, Marcel Kool, Dominic Sturm, David T W Jones, Ruth Tatevossian, Berangere Lombard, Damarys Loew, Daniel Bowers, Anne Bendel, Sonia Partap, Murali Chintagumpala, John Crawford, Nicholas G Gottardo, Amy Smith, Christelle Dufour, Stefan Rutkowski, Michael Grotzer, Mark Remke, Stephanie 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
Institutions: St. Jude Children's Research Hospital, European Molecular Biology Laboratory, European Molecular Biology Laboratory, Université Paris Sciences et Lettres, Institut Curie, The University of Queensland, Institute for Molecular Bioscience, Dana-Farber Cancer Institute, German Cancer Research Center, Hopp Children's Cancer Center Heidelberg, Princess Máxima Center, The University of Texas Southwestern Medical Center, Children's Minnesota, Stanford University, Baylor College of Medicine, University of California San Diego, Rady Children's Hospital-San Diego, Princess Margaret Hospital for Children, Perth Children's Hospital, Arnold Palmer Hospital for Children, Institut Gustave Roussy, University Medical Center Hamburg-Eppendorf, University of Zurich, University Children's Hospital Zurich, Düsseldorf University Hospital, Hôpital Necker-Enfants Malades, Burdenko Neurosurgery Institute, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,132
OpenAlex ID: W3112514136