# Dissecting the Spectrum, Prevalence, and Molecular Mechanisms of Enhancer Hijacking in Medulloblastoma

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $410,606

## Abstract

PROJECT SUMMARY
Medulloblastoma (MB) is the most common malignant brain tumor in children. Although aggressive
treatments have improved outcomes, many MB patients still die of their disease, and survivors suffer
severe long-term side effects from therapy. Thus, more effective and less toxic treatments are
desperately needed. Genomics has established that MB is not a single entity, but more accurately a
collection of biologically and clinically distinct diseases designated as subgroups: WNT, SHH, Group 3,
and Group 4. In contrast to WNT and SHH subgroup MBs, the molecular basis of Group 3 and Group 4,
the most common and aggressive forms of MB, remains only partially understood. We recently
discovered a series of recurrent structural genomic alterations that relocate normally distal highly active
enhancers proximal to the genes encoding GFI1 and GFI1B, resulting in profound GFI1/GFI1B over-
expression in affected Group 3 and Group 4 MBs. The remarkable but complex nature of this genetic-
epigenetic interplay mitigated by structural alterations leading to misappropriation of enhancer activity
and oncogene deregulation, prompted us to designate this phenomenon `enhancer hijacking'. Intensive
sequencing efforts have determined that Group 3 and Group 4 MBs exhibit a paucity of recurrent gene-
level mutations, yet often harbor extensive structural alterations of unknown significance. In light of these
findings, we hypothesize that enhancer hijacking plays a prominent role in the etiology of Group 3 and
Group 4 and strategies aimed to systematically identify and mechanistically characterize these events
will advance our understanding of these poorly defined subgroups. To test this hypothesis, we propose
to: (i) systematically investigate the spectrum and prevalence of enhancer hijacking in MB subgroups; (ii)
elucidate the mechanistic basis of prominent enhancer hijacking events contributing to MB, including the
role of 3-dimensional genome organization; and (iii) functionally recapitulate MB-associated enhancer
hijacking in relevant cellular contexts. The results from these studies will extend beyond poorly
understood MB subgroups and aim to yield essential insights into the molecular mechanisms governing
oncogene deregulation in cancer and provide a deeper understanding into how noncoding genomic
variation contributes to malignancy.

## Key facts

- **NIH application ID:** 10247688
- **Project number:** 5R01CA232143-04
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Paul Northcott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,606
- **Award type:** 5
- **Project period:** 2018-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247688

## Citation

> US National Institutes of Health, RePORTER application 10247688, Dissecting the Spectrum, Prevalence, and Molecular Mechanisms of Enhancer Hijacking in Medulloblastoma (5R01CA232143-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10247688. Licensed CC0.

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