# Characterization of ELP1 as a novel SHH medulloblastoma predisposition gene

> **NIH NIH P01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $348,718

## Abstract

PROJECT SUMMARY
Medulloblastoma (MB) is among the most common malignant childhood brain tumors. Although
aggressive treatments have improved outcomes, too many affected children still die of their disease, and
survivors often suffer from severe long-term side effects of therapy. Extensive molecular and biological
heterogeneity underlying MB has been described, culminating in the recognition of consensus molecular
subgroups – WNT, SHH, Group 3, and Group 4 – each of which is associated with divergent genomic
landscapes, patient demographics, and clinical outcomes. Although somatically altered genes and
biological pathways are well annotated, comprehensive understanding of genetic predisposition to MB
has lagged behind. We recently investigated germline loss-of-function (LoF) across all protein-coding
genes in a series of >1,000 MB patients. This unbiased approach uncovered highly significant deleterious
germline variants in ELP1 that were specific to childhood SHH-MB patients and twice as common as
pathogenic variants affecting known MB-associated genes. ELP1 encodes a scaffolding subunit of
Elongator, a multi-subunit protein complex (ELP1-6) that chemically modifies wobble U34 uridines in the
anticodon loop of tRNAs to enable efficient translational elongation and maintenance of physiological
protein folding dynamics. ELP1-associated tumors exhibited frequent co-occurrence of somatic PTCH1
mutations and amplifications of PPM1D and MDM4, suggesting germline ELP1 LoF variants cooperate
with constitutive activation of SHH and/or TP53 signaling to promote MB development. ELP1-associated
SHH-MBs 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. Based on these findings, we hypothesize that
ELP1 is a novel cancer predisposition gene and aim to functionally elucidate the developmental,
biochemical, and molecular mechanisms by which pathogenic ELP1 LoF promotes SHH-MB. To test this
hypothesis, we propose to (i) evaluate the requirement for Elp1 during cerebellar development; (ii)
validate the tumor suppressive role of Elp1 in SHH-MB; and (iii) determine the impact of MB-associated
Elp1 LoF on translation and the proteome. These studies will be conducted in a series of novel Elp1+/-
transgenic mice, primary cells derived from the developing mouse cerebellum, and genetically faithful
SHH-MB patient-derived xenografts. Successful execution of this research program will effectively link
germline ELP1 LoF to the biochemical and molecular mechanisms governing SHH-MB pathogenesis.
Outcomes of the proposed research will be of broad interest, extending to scientists and clinicians with
an interest in cancer predisposition, as well as basic researchers studying the fundamentals of
translational regulation and protein homeostasis and their role in human disease.

## Key facts

- **NIH application ID:** 10479010
- **Project number:** 5P01CA096832-17
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Paul Northcott
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $348,718
- **Award type:** 5
- **Project period:** 2003-04-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10479010

## Citation

> US National Institutes of Health, RePORTER application 10479010, Characterization of ELP1 as a novel SHH medulloblastoma predisposition gene (5P01CA096832-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10479010. Licensed CC0.

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