Germline Elongator mutations in Sonic Hedgehog medulloblastoma

doi:10.1038/s41586-020-2164-5

. 2020 Apr;580(7803):396-401.

doi: 10.1038/s41586-020-2164-5. Epub 2020 Apr 1.

Germline Elongator mutations in Sonic Hedgehog medulloblastoma

Sebastian M Waszak^#¹, Giles W Robinson^#², Brian L Gudenas³, Kyle S Smith³, Antoine Forget⁴, Marija Kojic⁵, Jesus Garcia-Lopez³, Jennifer Hadley³, Kayla V Hamilton⁶, Emilie Indersie⁴, Ivo Buchhalter⁷, Jules Kerssemakers⁷, Natalie Jäger^{8

9}, Tanvi Sharma^{8

9}, Tobias Rausch¹, Marcel Kool^{8

9

10}, Dominik Sturm^{8

11}, David T W Jones^{8

11}, Aksana Vasilyeva¹², Ruth G Tatevossian¹³, Geoffrey Neale¹⁴, Bérangère Lombard¹⁵, Damarys Loew¹⁵, Joy Nakitandwe¹³, Michael Rusch¹⁶, Daniel C Bowers¹⁷, Anne Bendel¹⁸, Sonia Partap¹⁹, Murali Chintagumpala²⁰, John Crawford^{21

22}, Nicholas G Gottardo²³, Amy Smith²⁴, Christelle Dufour²⁵, Stefan Rutkowski²⁶, Tone Eggen²⁷, Finn Wesenberg²⁸, Kristina Kjaerheim²⁸, Maria Feychting²⁹, Birgitta Lannering³⁰, Joachim Schüz³¹, Christoffer Johansen^{32

33}, Tina V Andersen³⁴, Martin Röösli³⁵, Claudia E Kuehni^{35

36}, Michael Grotzer³⁷, Marc Remke³⁸, Stéphanie Puget³⁹, Kristian W Pajtler^{8

9

40}, Till Milde^{8

40

41}, Olaf Witt^{8

40

41}, Marina Ryzhova⁴², Andrey Korshunov^{43

44}, Brent A Orr¹³, David W Ellison¹³, Laurence Brugieres²⁵, Peter Lichter⁴⁵, Kim E Nichols⁶, Amar Gajjar², Brandon J Wainwright⁵, Olivier Ayrault⁴, Jan O Korbel⁴⁶, Paul A Northcott⁴⁷, Stefan M Pfister^{48

49

50}

Affiliations

¹ European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
² Department of Oncology, Division of Neuro-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
³ Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
⁴ Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁶ Department of Oncology, Division of Cancer Predisposition, St Jude Children's Research Hospital, Memphis, TN, USA.
⁷ Omics IT and Data Management Core Facility (W610), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁹ Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
¹¹ Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Cancer Center Administration, St Jude Children's Research Hospital, Memphis, TN, USA.
¹³ Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁴ Hartwell Center, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁵ Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France.
¹⁶ Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁷ Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA.
¹⁸ Department of Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, Minnesota, MN, USA.
¹⁹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
²⁰ Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
²¹ Department of Neurosciences, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.
²² Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.
²³ Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital and Brain Tumour Research Programme, Telethon Kids Institute, Perth, Western Australia, Australia.
²⁴ Arnold Palmer Hospital Center for Children's Cancer, Orlando, FL, USA.
²⁵ Gustave Roussy, Université Paris-Saclay, Department of Pediatric and Adolescent Oncology, Villejuif, France.
²⁶ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁷ The Cancer Registry of Norway, Majorstuen, Oslo, Norway.
²⁸ Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
²⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁰ Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
³¹ Section of Environment and Radiation, International Agency for Research on Cancer (IARC), Lyon, France.
³² Oncology Clinic, Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
³³ Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
³⁴ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
³⁵ Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine University of Bern, Bern, Switzerland.
³⁶ Department of Paediatric Haematology and Oncology, University Children's Hospital, Bern, Switzerland.
³⁷ University Children's Hospital of Zurich, Zurich, Switzerland.
³⁸ Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
³⁹ Department of Pediatric Neurosurgery, Necker Hospital, Université de Paris, Paris, France.
⁴⁰ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
⁴¹ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴² Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
⁴³ Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁴ Department of Neuropathology, University Hospital, Heidelberg, Germany.
⁴⁵ Division of Molecular Genetics, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
⁴⁶ European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany. jan.korbel@embl.org.
⁴⁷ Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.northcott@stjude.org.
⁴⁸ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
⁴⁹ Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
⁵⁰ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. s.pfister@kitz-heidelberg.de.

^# Contributed equally.

PMID: 32296180
PMCID: PMC7430762
DOI: 10.1038/s41586-020-2164-5

Germline Elongator mutations in Sonic Hedgehog medulloblastoma

Sebastian M Waszak et al. Nature. 2020 Apr.

. 2020 Apr;580(7803):396-401.

doi: 10.1038/s41586-020-2164-5. Epub 2020 Apr 1.

Authors

Affiliations

¹ European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
² Department of Oncology, Division of Neuro-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
³ Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
⁴ Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁶ Department of Oncology, Division of Cancer Predisposition, St Jude Children's Research Hospital, Memphis, TN, USA.
⁷ Omics IT and Data Management Core Facility (W610), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁹ Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
¹¹ Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Cancer Center Administration, St Jude Children's Research Hospital, Memphis, TN, USA.
¹³ Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁴ Hartwell Center, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁵ Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France.
¹⁶ Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁷ Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA.
¹⁸ Department of Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, Minnesota, MN, USA.
¹⁹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
²⁰ Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
²¹ Department of Neurosciences, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.
²² Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.
²³ Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital and Brain Tumour Research Programme, Telethon Kids Institute, Perth, Western Australia, Australia.
²⁴ Arnold Palmer Hospital Center for Children's Cancer, Orlando, FL, USA.
²⁵ Gustave Roussy, Université Paris-Saclay, Department of Pediatric and Adolescent Oncology, Villejuif, France.
²⁶ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁷ The Cancer Registry of Norway, Majorstuen, Oslo, Norway.
²⁸ Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
²⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁰ Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
³¹ Section of Environment and Radiation, International Agency for Research on Cancer (IARC), Lyon, France.
³² Oncology Clinic, Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
³³ Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
³⁴ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
³⁵ Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine University of Bern, Bern, Switzerland.
³⁶ Department of Paediatric Haematology and Oncology, University Children's Hospital, Bern, Switzerland.
³⁷ University Children's Hospital of Zurich, Zurich, Switzerland.
³⁸ Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
³⁹ Department of Pediatric Neurosurgery, Necker Hospital, Université de Paris, Paris, France.
⁴⁰ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
⁴¹ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴² Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
⁴³ Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁴ Department of Neuropathology, University Hospital, Heidelberg, Germany.
⁴⁵ Division of Molecular Genetics, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
⁴⁶ European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany. jan.korbel@embl.org.
⁴⁷ Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.northcott@stjude.org.
⁴⁸ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
⁴⁹ Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
⁵⁰ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. s.pfister@kitz-heidelberg.de.

^# Contributed equally.

PMID: 32296180
PMCID: PMC7430762
DOI: 10.1038/s41586-020-2164-5

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 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 (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 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) 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.

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Conflict of interest statement

Competing Interests

The authors declare no competing interests.

Figures

**Extended Data Figure 1.. Case-control germline loss-of-function (LoF) variant burden analysis.**
**a-d.** Case-control germline rare LoF variant association analysis in pediatric MB subgroups vs pediatric controls (CEFALO) using burden tests (implemented in SKAT). P values were corrected for multiple testing using Bonferroni correction. **e-h.** Case-control germline rare LoF variant association analysis in pediatric MB subgroups vs 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 pediatric MB vs adult controls (gnomAD). **j-l.** Case-control germline LoF burden analysis in infant (j), childhood (k), and adult (1) MB_SHH vs adult controls (gnomAD).

**Extended Data Figure 2.. Congenital radioulnar synostosis**
Right arm X-rays of (a) an unaffected child and (b) the *ELP1*-associated MB_SHH patient SJMBWES339.

**Extended Data Figure 3.. Molecular MB_SHH subtypes**
a. DNA methylation-based UMAP plot of MB_SHH with inference of MB_SHH 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. e. Recurrent somatic copy-number alterations in *ELP1*-associated SHHα.

**Extended Data Figure 4.. Inference of somatic evolution in *ELP1*-associated MB_SHH.**
a. Possible genetic models explaining the relationship between germline *ELP1* mutation status and two somatic mutational events (*PTCH1*_mut, and loss of chromosome 9q) in MB_SHH. b. Posterior probabilities derived from Bayesian network analysis of all possible genetic models shown in a and data for 230 MB_SHH patients.

**Extended Data Figure 5.. Molecular features of *ELP1*-associated medulloblastoma**
a. *ELP1* expression stratified by consensus MB subgroup (n=208 patients). P value was calculated using likelihood ratio tests. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range. b. *ELP1* expression stratified by molecular MB_SHH subtype (n=90 patients). P value was calculated using likelihood ratio tests. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range. c. *ELP1* expression stratified by germline *ELP1* mutation status (n=90 patients). P value was calculated using likelihood ratio tests. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range. d. Differential gene expression in *ELP1*_mut (n=10) and *ELP1*_wt SHHα (n=9). P values were derived from models that use negative binomal 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 MB_SHH proteomes. P values were calculated using a two-sided Mann-Whitney U-test. **P<0.01; ns P>0.05. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range. g. GSEA-based enrichment of the Elongator complex in MB_SHH proteomes. P value was calculated using a two-sided Mann-Whitney U-test. ***P<0.001; Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range.

**Extended Data Figure 6.. Unsupervised multi-omics factor integration analysis of MB_SHH**
a. Overview of input samples and data types. b. Latent factors variance summary across data types. c. Somatic/germline gene alterations contributing 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. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range. e. Functional enrichment of LF1-ranked proteins and mRNAs.

**Extended Data Figure 7.. Quantification of tRNA modifications in *ELP1*-associated MB_SHH**
a. Quantification of mcm⁵U nucleosides in *ELP1*_mut MB_SHH PDX (n=4 biologically independent samples) and *ELP1*_wt MB_SHH PDX (n=4 biologically independent samples). Mean and standard errors are shown. P value was calculated using a two-sided Welch t-test. *P<0.05. b. Quantification of m¹A nucleosides in *ELP1*_mut MB_SHH PDX (n=4 biologically independent samples) and *ELP1*_wt MB_SHH PDX (n=4 biologically independent samples). Mean and standard errors are shown. P value was calculated using a two-sided Welch i-test. *ns>0.05. c. Quantification of m⁷G nucleosides in *ELP1*_mut MB_SHH PDX (n=4 biologically independent samples) and *ELP1*_wt MB_SHH PDX (n=4 biologically independent samples). Mean and standard errors are shown. P value was calculated using a two-sided Welch t-test. ns P>0.05.

**Extended Data Figure 8.. Spatio-temporal *ELP1* expression in human and mouse.**
a. *ELP1* expression in adult human tissues (n=9-653 donors per tissue). Violin plots depict kernel density estimates and represent the density distribution b. *ELP1* expression during human brain development (n=3-12 donors per tissue and time point). Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range. c. *ELP1* expression during human organ development. Shaded areas define 90% confidence intervals (n=18-58 donors per tissue). d. *Elp1* expression during mouse cerebellum development (n=27 animals). Center values and error bars define the mean expression of cells with non-zero *ELP1* expression and standard error of the mean.

**Figure 1.. *ELP1*-associated medulloblastoma**
a. QQ plot for LoF burden testing based on 171 pediatric MB_SHH cases and 288 pediatric controls. P values were adjusted for multiple testing based on Bonferroni correction. b. Germline *ELP1* mutation profile in MB_SHH patients. c. Frequency of germline *ELP1* LoF variants in the MB discovery cohort. d. Frequency of germline *ELP1* LoF variants in a prospective pediatric MB_SHH cohort. e. Frequency of known and recurrent genetic disorders in pediatric MB_SHH. f. Frequency of germline *ELP1* LoF variants in MB_SHH, pediatric/adult pan-cancer, and control cohorts. g. Age at diagnosis for MB_SHH patients stratified by known genetic disorders. P values were calculated using a two-sided Mann–Whitney U-test. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range.

**Figure 2.. Familial transmission of *ELP1*-associated medulloblastoma**
Pedigrees and family history for two *ELP1*-associated MB_SHH patients. Circles, females; squares, males; diamond, sex unspecified; slash, deceased. Index patients are marked with an arrow. a. SJMBWES339. b. SJMBWES401.

**Figure 3.. Somatic mutation landscape of *ELP1*-associated medulloblastoma**
a. Loss-of-heterozygosity (LOH) at the *ELP1* locus for patients with germline *ELP1* LoF variants (n=29 germline and n=29 MB samples). P values for LOH in MBs were calculated using a two-sided binomial test; *P<0.05. P value for the proportion of *ELP1* LOH events was calculated using a two-sided binomial test. b. Germline *ELP1* mutation status stratified by molecular MB_SHH subtypes. c. Somatic mutation landscape of MB_SHH subtypes. d. Association between germline *ELP1* LoF variants and somatic gene alterations (n=238 MB_SHH). P values were calculated using Bayesian logistic regression analysis, likelihood ratio tests, and adjusted for multiple testing based on FDR correction. e. Association between germline *ELP1* LoF variants and somatic chromosomal alterations (n=238 MB_SHH). P values were calculated using Bayesian logistic regression analysis, likelihood ratio tests, and adjusted for multiple testing based on FDR correction. Proposed three-step model of somatic evolution in *ELP1*-associated MB_SHH. f. Histological classification within molecular SHHα subtypes. g. Overall survival within molecular SHHα subtypes based on Kaplan-Meier estimator and log-rank test.

**Figure 4.. Molecular features of *ELP1*-associated medulloblastoma**
a. Differential gene expression between *ELP1*_mut MB_SHH (n=10) and *ELP1*_wt, MB_SHH (n=90). P values were derived from models that use negative binomal test statistics and were adjusted for multiple testing based on FDR correction. b. Functional gene enrichment in *ELP1*_mut MB_SHH. c. Differential protein expression between *ELP1*_mut MB_SHH (n=6) and *ELP1*_wt, MB_SHH (n=9). P values were derived from linear models that use empirical Bayes statistics and were adjusted for multiple testing based on FDR correction. d. Functional protein enrichment in *ELP1*_mut MB_SHH. e. Gene expression of Elongator subunits in *ELP1*_mut MB_SHH (n=10) and *ELP1*_mut MB_SHH (n=80) and protein expression of Elongator subunits in *ELP1*_mut MB_SHH (n=6) and *ELP1*_mut MB_SHH (n=9). P values were derived from models that use negative binomal test statistics and empirical Bayes statistics. *P<0.05, **P<0.01, ***P<0.001, n.s. P>0.10. f. Quantification of ncm⁵U nucleosides in *ELP1*_mut MB_SHH (n=4 biologically independent samples) and *ELP1*_wt MB_SHH (n=4 biologically independent samples). P values were calculated using two-sided Welch t-tests. Mean values and standard errors are shown. **P<0.01. g. Quantification of mcm⁵s²U nucleosides in *ELP1*_mut MB_SHH (n=4 biologically independent samples) and *ELP1*_wt MB_SHH (n=4 biologically independent samples). P values were calculated using two-sided Welch t-tests. Mean values and standard errors are shown. **P<0.01. h. Codon usage bias (ARSCU) in *ELP1*_mut MB_SHH (n=6) vs *ELP1*_wt MB_SHH (n=9). P values were calculated using two-sided Mann–Whitney U-tests and adjusted for multiple testing using FDR correction. i. Codon usage bias (AA- vs AG-ending codons) in *ELP1*_mut MB_SHH (n=6) vs *ELP1*_wt MB_SHH (n=9). P value was calculated using a two-sided Mann–Whitney U-test. ***P<0.001. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range. j. Protein size distribution in *ELP1*_mut MB_SHH (n=6) vs *ELP1*_wt MB_SHH (n=9). P values were calculated using a two-sided Mann–Whitney U-test. ***P<0.001. Boxes show median, first and third quartile, and whiskers extend to 1.5× the interquartile range.

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References

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1. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui CH, Nichols KE & Downing JR Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373, 2336–2346, doi:10.1056/NEJMoa1508054 (2015). - DOI - PMC - PubMed
1. Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Grand KB, Brugieres L, Jones DTW, Pajtler KW, Morrissy AS, Kool M, Sturm D, Chavez L, Ernst A, Brabetz S, Hain M, Zichner T, Segura-Wang M, Weischenfeldt J, Rausch T, Mardin BR, Zhou X, Baciu C, Lawerenz C, Chan JA, Varlet P, Guerrini-Rousseau L, Fults DW, Grajkowska W, Hauser P, Jabado N, Ra YS, Zitterbart K, Shringarpure SS, De La Vega FM, Bustamante CD, Ng HK, Perry A, MacDonald TJ, Hernaiz Driever P, Bendel AE, Bowers DC, McCowage G, Chintagumpala MM, Cohn R, Hassall T, Fleischhack G, Eggen T, Wesenberg F, Feychting M, Lannering B, Schuz J, Johansen C, Andersen TV, Roosli M, Kuehni CE, Grotzer M, Kjaerheim K , Monoranu CM, Archer TC, Duke E, Pomeroy SL, Shelagh R, Frank S, Sumerauer D, Scheurlen W, Ryzhova MV, Milde T, Kratz CP, Samuel D, Zhang J, Solomon DA, Marra M, Eils R, Bartram CR, von Hoff K, Rutkowski S, Ramaswamy V, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Malkin D, Gajjar A, Korbel JO & Pfister SM Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19, 785–798, doi:10.1016/S1470-2045(18)30242-0 (2018). - DOI - PMC - PubMed
1. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C , Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ , Ra YS, Kumabe T, Lopez-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpena-Diazconti M, Chico Ponce de Leon F, Robinson S, Zapotocky M , Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB., Rutka JT., Bader GD., Reimand J, Goldenberg A, Ramaswamy V & Taylor MD. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 31, 737–754 e736, doi:10.1016/j.ccell.2017.05.005 (2017). - DOI - PMC - PubMed
1. Hawer H, Hammermeister A, Ravichandran KE, Glatt S, Schaffrath R & Klassen R Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer. Genes (Basel) 10, doi:10.3390/genes10010019 (2018). - DOI - PMC - PubMed

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[1] Grobner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, Johann PD , Balasubramanian GP, Segura-Wang M, Brabetz S, Bender S, Hutter B, Sturm D, Pfaff E, Hubschmann D, Zipprich G, Heinold M, Eils J, Lawerenz C, Erkek S, Lambo S, Waszak S, Blattmann C, Borkhardt A, Kuhlen M, Eggert A, Fulda S, Gessler M, Wegert J, Kappler R, Baumhoer D, Burdach S, Kirschner-Schwabe R, Kontny U, Kulozik AE, Lohmann D, Hettmer S, Eckert C, Bielack S, Nathrath M, Niemeyer C, Richter GH, Schulte J, Siebert R, Westermann F, Molenaar JJ, Vassal G, Witt H, Project IP-S, Project IM-S, Burkhardt B, Kratz CP, Witt O, van Tilburg CM, Kramm CM, Fleischhack G, Dirksen U, Rutkowski S, Fruhwald M, von Hoff K, Wolf S, Klingebiel T, Koscielniak E, Landgraf P, Koster J, Resnick AC, Zhang J, Liu Y, Zhou X, Waanders AJ, Zwijnenburg DA, Raman P, Brors B, Weber UD, Northcott PA, Pajtler KW, Kool M, Piro RM, Korbel JO, Schlesner M, Eils R, Jones DTW, Lichter P, Chavez L, Zapatka M & Pfister SM The landscape of genomic alterations across childhood cancers. Nature 555, 321–327, doi:10.1038/nature25480 (2018). - DOI - PubMed

[2] Grobner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, Johann PD , Balasubramanian GP, Segura-Wang M, Brabetz S, Bender S, Hutter B, Sturm D, Pfaff E, Hubschmann D, Zipprich G, Heinold M, Eils J, Lawerenz C, Erkek S, Lambo S, Waszak S, Blattmann C, Borkhardt A, Kuhlen M, Eggert A, Fulda S, Gessler M, Wegert J, Kappler R, Baumhoer D, Burdach S, Kirschner-Schwabe R, Kontny U, Kulozik AE, Lohmann D, Hettmer S, Eckert C, Bielack S, Nathrath M, Niemeyer C, Richter GH, Schulte J, Siebert R, Westermann F, Molenaar JJ, Vassal G, Witt H, Project IP-S, Project IM-S, Burkhardt B, Kratz CP, Witt O, van Tilburg CM, Kramm CM, Fleischhack G, Dirksen U, Rutkowski S, Fruhwald M, von Hoff K, Wolf S, Klingebiel T, Koscielniak E, Landgraf P, Koster J, Resnick AC, Zhang J, Liu Y, Zhou X, Waanders AJ, Zwijnenburg DA, Raman P, Brors B, Weber UD, Northcott PA, Pajtler KW, Kool M, Piro RM, Korbel JO, Schlesner M, Eils R, Jones DTW, Lichter P, Chavez L, Zapatka M & Pfister SM The landscape of genomic alterations across childhood cancers. Nature 555, 321–327, doi:10.1038/nature25480 (2018). - DOI - PubMed

[3] Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui CH, Nichols KE & Downing JR Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373, 2336–2346, doi:10.1056/NEJMoa1508054 (2015). - DOI - PMC - PubMed

[4] Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui CH, Nichols KE & Downing JR Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373, 2336–2346, doi:10.1056/NEJMoa1508054 (2015). - DOI - PMC - PubMed

[5] Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Grand KB, Brugieres L, Jones DTW, Pajtler KW, Morrissy AS, Kool M, Sturm D, Chavez L, Ernst A, Brabetz S, Hain M, Zichner T, Segura-Wang M, Weischenfeldt J, Rausch T, Mardin BR, Zhou X, Baciu C, Lawerenz C, Chan JA, Varlet P, Guerrini-Rousseau L, Fults DW, Grajkowska W, Hauser P, Jabado N, Ra YS, Zitterbart K, Shringarpure SS, De La Vega FM, Bustamante CD, Ng HK, Perry A, MacDonald TJ, Hernaiz Driever P, Bendel AE, Bowers DC, McCowage G, Chintagumpala MM, Cohn R, Hassall T, Fleischhack G, Eggen T, Wesenberg F, Feychting M, Lannering B, Schuz J, Johansen C, Andersen TV, Roosli M, Kuehni CE, Grotzer M, Kjaerheim K , Monoranu CM, Archer TC, Duke E, Pomeroy SL, Shelagh R, Frank S, Sumerauer D, Scheurlen W, Ryzhova MV, Milde T, Kratz CP, Samuel D, Zhang J, Solomon DA, Marra M, Eils R, Bartram CR, von Hoff K, Rutkowski S, Ramaswamy V, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Malkin D, Gajjar A, Korbel JO & Pfister SM Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19, 785–798, doi:10.1016/S1470-2045(18)30242-0 (2018). - DOI - PMC - PubMed

[6] Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Grand KB, Brugieres L, Jones DTW, Pajtler KW, Morrissy AS, Kool M, Sturm D, Chavez L, Ernst A, Brabetz S, Hain M, Zichner T, Segura-Wang M, Weischenfeldt J, Rausch T, Mardin BR, Zhou X, Baciu C, Lawerenz C, Chan JA, Varlet P, Guerrini-Rousseau L, Fults DW, Grajkowska W, Hauser P, Jabado N, Ra YS, Zitterbart K, Shringarpure SS, De La Vega FM, Bustamante CD, Ng HK, Perry A, MacDonald TJ, Hernaiz Driever P, Bendel AE, Bowers DC, McCowage G, Chintagumpala MM, Cohn R, Hassall T, Fleischhack G, Eggen T, Wesenberg F, Feychting M, Lannering B, Schuz J, Johansen C, Andersen TV, Roosli M, Kuehni CE, Grotzer M, Kjaerheim K , Monoranu CM, Archer TC, Duke E, Pomeroy SL, Shelagh R, Frank S, Sumerauer D, Scheurlen W, Ryzhova MV, Milde T, Kratz CP, Samuel D, Zhang J, Solomon DA, Marra M, Eils R, Bartram CR, von Hoff K, Rutkowski S, Ramaswamy V, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Malkin D, Gajjar A, Korbel JO & Pfister SM Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19, 785–798, doi:10.1016/S1470-2045(18)30242-0 (2018). - DOI - PMC - PubMed

[7] Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C , Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ , Ra YS, Kumabe T, Lopez-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpena-Diazconti M, Chico Ponce de Leon F, Robinson S, Zapotocky M , Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB., Rutka JT., Bader GD., Reimand J, Goldenberg A, Ramaswamy V & Taylor MD. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 31, 737–754 e736, doi:10.1016/j.ccell.2017.05.005 (2017). - DOI - PMC - PubMed

[8] Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C , Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ , Ra YS, Kumabe T, Lopez-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpena-Diazconti M, Chico Ponce de Leon F, Robinson S, Zapotocky M , Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB., Rutka JT., Bader GD., Reimand J, Goldenberg A, Ramaswamy V & Taylor MD. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 31, 737–754 e736, doi:10.1016/j.ccell.2017.05.005 (2017). - DOI - PMC - PubMed

[9] Hawer H, Hammermeister A, Ravichandran KE, Glatt S, Schaffrath R & Klassen R Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer. Genes (Basel) 10, doi:10.3390/genes10010019 (2018). - DOI - PMC - PubMed

[10] Hawer H, Hammermeister A, Ravichandran KE, Glatt S, Schaffrath R & Klassen R Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer. Genes (Basel) 10, doi:10.3390/genes10010019 (2018). - DOI - PMC - PubMed

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Germline Elongator mutations in Sonic Hedgehog medulloblastoma

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Germline Elongator mutations in Sonic Hedgehog medulloblastoma

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