PXD016832-1

PXD016832 is an original dataset announced via ProteomeXchange.

Title	Elongator complex deficiency in sonic hedgehog medulloblastoma
Description	Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.
HostingRepository	PRIDE
AnnounceDate	2020-04-23
AnnouncementXML	Submission_2020-04-22_23:20:05.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Valentin SABATET
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2019-12-19 05:32:52	ID requested
⏵ 1	2020-04-22 23:20:07	announced

Waszak SM, Robinson GW, Gudenas BL, Smith KS, Forget A, Kojic M, Garcia-Lopez J, Hadley J, Hamilton KV, Indersie E, Buchhalter I, Kerssemakers J, J, ä, ger N, Sharma T, Rausch T, Kool M, Sturm D, Jones DTW, Vasilyeva A, Tatevossian RG, Neale G, Lombard B, Loew D, Nakitandwe J, Rusch M, Bowers DC, Bendel A, Partap S, Chintagumpala M, Crawford J, Gottardo NG, Smith A, Dufour C, Rutkowski S, Eggen T, Wesenberg F, Kjaerheim K, Feychting M, Lannering B, Sch, ü, z J, Johansen C, Andersen TV, R, ö, ö, sli M, Kuehni CE, Grotzer M, Remke M, Puget S, Pajtler KW, Milde T, Witt O, Ryzhova M, Korshunov A, Orr BA, Ellison DW, Brugieres L, Lichter P, Nichols KE, Gajjar A, Wainwright BJ, Ayrault O, Korbel JO, Northcott PA, Pfister SM, Germline Elongator mutations in Sonic Hedgehog medulloblastoma. Nature, 580(7803):396-401(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: Meduloblastoma, SHH, Elongator complex, ELP1

Damarys Loew
contact affiliation	Head of the Curie Institute Mass Spectrometry Platform
contact email	damarys.loew@curie.fr
lab head
Valentin SABATET
contact affiliation	Curie Institute
contact email	valentin.sabatet@curie.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD016832
     1. Label: PRIDE project
     2. Name: Elongator complex deficiency in sonic hedgehog medulloblastoma