Journal
NATURE
Volume 580, Issue 7803, Pages 396-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2164-5
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Funding
- PedBrain Tumor Project - German Cancer Aid [109252]
- German Federal Ministry of Education and Research (BMBF) [01KU1201A, 01KU1201C]
- BMBF grant BioTop [01EK1502A, 01EK1502B]
- BMBF grant ICGC-DE-Mining [01KU1505F]
- BMBF grant MedSys [0315416C]
- BMBF grant NGFNplus [01GS0883]
- European Research Council Starting Grant [336045]
- European Commission [260791]
- Swiss National Science Foundation Early Postdoc Mobility Fellowship [P2ELP3_155365]
- EMBO Long-Term Fellowship [ALTF 755-2014]
- Helmholtz Association Research Grant (Germany)
- RSF Research Grant [18-45-06012]
- Sontag Foundation Distinguished Scientist Award
- National Cancer Institute [R01CA232143-01]
- American Association for Cancer Research (NextGen Grant for Transformative Cancer Research)
- Brain Tumour Charity (Quest for Cures and Clinical Biomarkers)
- American Lebanese Syrian Associated Charities (ALSAC)
- St Jude
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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 (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 SHH alpha 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 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 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. Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma.
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