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Germline Elongator mutations in Sonic Hedgehog medulloblastoma

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 systems7,8,9. 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.

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Fig. 1: ELP1-associated medulloblastoma.
Fig. 2: Familial transmission of ELP1-associated medulloblastoma.
Fig. 3: Somatic mutation landscape of ELP1-associated medulloblastoma.
Fig. 4: Molecular features of ELP1-associated medulloblastoma.

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Data availability

Germline and tumour DNA sequencing, RNA sequencing, and DNA methylation array datasets have been deposited to the European Genome-phenome Archive (EGA) with accession number EGAS00001004126. Proteomic datasets have been deposited to the Proteomics Identifications Database (PRIDE) with accession number PXD016832. Molecular datasets can be freely explored using the St Jude PeCan Data Portal (https://pecan.stjude.cloud/proteinpaint/study/MB-ELP1). Source Data for Figs. 1, 3 and 4 are provided with the paper. All other data are available from the corresponding authors upon reasonable request.

Code availability

All custom code used to generate the data in this study is available upon reasonable request.

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Acknowledgements

This project was supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium (ICGC), funded by the German Cancer Aid (109252), the German Federal Ministry of Education and Research (BMBF) (01KU1201A, 01KU1201C), and through BMBF grants BioTop (01EK1502A, 01EK1502B), ICGC-DE-Mining (01KU1505F), MedSys (0315416C) and NGFNplus (01GS0883). J.O.K. was supported by a European Research Council Starting Grant (336045) and acknowledges EurocanPlatform (260791) funding from the European Commission. S.M.W. was supported by a Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2ELP3_155365) and an EMBO Long-Term Fellowship (ALTF 755-2014). A.K. is supported by the Helmholtz Association Research Grant (Germany). M.R. is supported by the RSF Research Grant no. 18-45-06012. We acknowledge the EMBL IT facilities for supporting the genomic analyses. P.A.N. is a Pew-Stewart Scholar for Cancer Research (Margaret and Alexander Stewart Trust) and recipient of The Sontag Foundation Distinguished Scientist Award. P.A.N. was also supported by the National Cancer Institute (R01CA232143-01), American Association for Cancer Research (NextGen Grant for Transformative Cancer Research), The Brain Tumour Charity (Quest for Cures and Clinical Biomarkers), the American Lebanese Syrian Associated Charities (ALSAC), and St Jude. From St Jude, we explicitly acknowledge the Hartwell Center, the Biorepository, members of the Department of Computational Biology, Clinical Genomics, the Diagnostic Biomarkers Shared Resource in the Department of Pathology, and the Center for In Vivo Imaging and Therapeutics. Where authors are identified as personnel of IARC/WHO, the authors alone are responsible for the views expressed in this Article, and they do not necessarily represent the decisions, policy, or views of IARC/WHO.

Author information

Authors and Affiliations

Authors

Contributions

Study conception: P.A.N., S.M.P. Study design: S.M.W., G.W.R., J.O.K., P.A.N., S.M.P. Sample collection, processing and patient data generation: G.W.R., J.G.-L., J.H., E.I., N.J., T.R., M. Kool, D.S., D.T.W.J., A.V., R.G.T., G.N., B. Lombard, D.L., J.N., M. Rusch, D.C.B., A.B., S. Partap, M.C., J.C., N.G.G., A.S., C.D., S.R., T.E., F.W., K.K., M.F., B. Lannering., J.S., C.J., T.V.A., M. Röösli, C.E.K., M.G., M. Remke, S. Puget, K.W.P., T.M., O.W., M. Ryzhova, A.K., B.A.O., D.W.E., L.B., A.G., O.A., P.A.N., S.M.P. Germline call-set and burden analysis: S.M.W., J.O.K. Pedigree analysis: K.V.H., K.E.N., G.W.R., L.B. Molecular classification: K.S.S., T.S. Somatic genome analysis: S.M.W., K.S.S., I.B., J.O.K. Transcriptome analysis: S.M.W., B.L.G. Proteome analysis: S.M.W., B.L.G., A.F., O.A., J.O.K. tRNA modification analysis: M. Kojic, B.J.W. Data deposition: I.B., J.K. Manuscript preparation (with feedback from all authors): S.M.W., G.W.R., B.L.G., K.S.S., J.O.K., P.A.N., S.M.P. Study supervision and funding: P.L., A.G., O.A., J.O.K., P.A.N., S.M.P.

Corresponding authors

Correspondence to Jan O. Korbel, Paul A. Northcott or Stefan M. Pfister.

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The authors declare no competing interests.

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Peer review information Nature thanks Xing Fan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Case–control germline LOF variant burden analysis.

ad, Case–control germline rare LOF variant association analysis in paediatric medulloblastoma subgroups versus paediatric controls (CEFALO) using burden tests (implemented in SKAT). P values were corrected for multiple testing using Bonferroni correction. eh, Case–control germline rare LOF variant association analysis in paediatric medulloblastoma subgroups versus adult controls (gnomAD) using burden tests (two-sided Fisher’s Exact tests). P values were corrected for multiple testing using Bonferroni correction. i, Case–control germline LOF burden analysis in paediatric medulloblastoma versus adult controls (gnomAD). jl, Case–control germline LOF burden analysis in infant (j), childhood (k) and adult (l) MBSHH versus adult controls (gnomAD).

Extended Data Fig. 2 Congenital radioulnar synostosis.

Right-arm X-rays of an unaffected child (control) and the ELP1-associated MBSHH patient (SJMBWES339).

Extended Data Fig. 3 Molecular MBSHH subtypes.

a, DNA methylation-based UMAP plot of MBSHH with inference of MBSHH subtypes (n = 262). b, Co-occurring and mutually exclusive somatic gene alterations in ELP1-associated medulloblastoma subtype SHHα. c, Co-occurring and mutually exclusive somatic chromosomal aberrations in ELP1-associated medulloblastoma subtype SHHα. d, Recurrent somatic copy-number alterations in ELP1-associated medulloblastoma subtype SHHα.

Extended Data Fig. 4 Inference of somatic evolution in ELP1-associated MBSHH.

a, Possible genetic models explaining the relationship between the germline status of ELP1 and two somatic mutational events (PTCH1 mutation and loss of chromosome arm 9q) in MBSHH. b, Posterior probabilities derived from Bayesian network analysis of all possible genetic models shown in a and data for 230 patients with MBSHH.

Extended Data Fig. 5 Molecular features of ELP1-associated MB.

a, Expression of ELP1 stratified by consensus medulloblastoma subgroup (n = 208 patients). P value was calculated using likelihood ratio tests. b, Expression of ELP1 stratified by molecular MBSHH subtype (n = 90 patients). P value was calculated using likelihood ratio tests. c, Expression of ELP1 stratified by germline ELP1 mutation status (n = 90 patients). P value was calculated using likelihood ratio tests. d, Differential gene expression in mutant (n = 10) and wild-type (n = 9) ELP1 SHHα. P values were derived from models that use negative binomial test statistics and were adjusted for multiple testing based on FDR correction. e, Functional gene enrichment in ELP1-associated SHHα. f, GSEA-based enrichment of UPR pathways in MBSHH proteomes. **P < 0.01, ns (not significant), P > 0.05, two-sided Mann–Whitney U-test. g, GSEA-based enrichment of the Elongator complex in MBSHH proteomes. ***P < 0.001, two-sided Mann–Whitney U-test. All box plots are as defined in Fig. 1g.

Extended Data Fig. 6 Unsupervised multi-omics factor integration analysis of MBSHH.

a, Overview of input samples and data types. b, Summary of variance in latent factors (LF1–LF4) across data types. c, Somatic and germline gene alterations that contribute to latent factor 1 (LF1). d, Association between germline ELP1 mutation status and LF1 score (n = 16 patients). P value was calculated using a two-sided Mann–Whitney U-test. Box plots are as defined in Fig. 1g. e, Functional enrichment of LF1-ranked proteins and mRNAs.

Extended Data Fig. 7 Quantification of tRNA modifications in ELP1-associated MBSHH.

a, Quantification of mcm5U nucleosides in mutant and wild-type ELP1 MBSHH PDX (n = 4 biologically independent samples for each). b, Quantification of m1A nucleosides in mutant and wild-type ELP1 MBSHH PDX (n = 4 biologically independent samples for each). c, Quantification of m7G nucleosides in mutant and wild-type ELP1 MBSHH PDX (n = 4 biologically independent samples for each). All data are mean and s.e.m. n.s., not significant (P > 0.05). *P < 0.05, two-sided Welch t-test.

Extended Data Fig. 8 Spatio-temporal ELP1 expression in human and mouse.

a, Expression of ELP1 in adult human tissues (n = 9–653 donors per tissue). Violin plots depict kernel density estimates and represent the density distribution. b, Expression of ELP1 during human brain development (n = 3–12 donors per tissue and time point). Box plots are as in Fig. 1g. c, Expression of ELP1 during human organ development. Shaded areas define 90% confidence intervals (n = 18–58 donors per tissue). d, Expression of Elp1 during mouse cerebellum development (n = 27 mice). Data are mean and s.e.m. expression of cells with non-zero ELP1 expression.

Supplementary information

Reporting Summary

Supplementary Table

Supplementary Table 1: Sample overview.

Supplementary Table

Supplementary Table 2: Germline ELP1 loss-of-function mutations in MBSHH patients.

Supplementary Table

Supplementary Table 3: Familial transmission of germline ELP1 LoF variants in parent-offspring trios.

Supplementary Table

Supplementary Table 4: ELP1-associated transcriptome (nmut=10 and nwt=80) and proteome (nmut=6 and nwt=9). P values were calculated using negative binomial tests and empirical Bayes statistics and adjusted for multiple testing using FDR correction.

Supplementary Table

Supplementary Table 5: Dynamic mass spectrometer parameters for ribonucleotides.

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Waszak, S., Robinson, G., Gudenas, B.L. et al. Germline Elongator mutations in Sonic Hedgehog medulloblastoma. Nature 580, 396–401 (2020). https://doi.org/10.1038/s41586-020-2164-5

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