# Deciphering the 3D genome of pediatric brain tumors

> **NIH NIH R03** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $391,151

## Abstract

Project Summary
Pediatric brain tumors are the most frequent cause of morbidity in children with solid tumors. Importantly, the
aggressive therapeutic regiments often lead to debilitating neurological effects. The realization that
developmental processes critical to brain development are also deregulated in cancer has provided new hope
for understanding and treating brain tumors. Indeed, single cell-RNAseq analyses have further demonstrated
the role of defects in lineage determination for pediatric brain tumors. To discover novel drivers of tumorigenesis,
we will focus on the function of three-dimensional (3D) genome folding in pediatric brain tumors. Indeed, 3D
chromatin interactions are involved in gene expression regulation, and changes in genome folding are linked to
cell identity acquisition during development. While there is increasing interest in elucidating the function of 3D
genome architecture during developmental processes and in cancer, how the 3D genome is organized in
different pediatric brain tumors and its roles in tumor formation and progression are unknown. We hypothesize
that disrupted 3D genome folding during embryonic or postnatal development alters gene expression leading to
abnormal cell differentiation and tumorigenesis in the developing brain. To test our hypothesis, we will
comprehensively interrogate the genomes of pediatric brain tumors for non-coding variants that may affect 3D
genome folding. We will use a deep-learning model called Akita that predicts 3D chromatin interaction
frequencies from genome sequence alone. Because Akita only requires DNA sequence as input, we can predict
the effect of any variant within a single framework that accommodates single-nucleotide variants (SNVs),
insertion/deletions (indels), and structural variation (SVs). Akita will be used with pediatric brain whole genome
sequences (WGS) from Gabriella Miller Kids First (KF) plus chromatin capture, epigenetic, and expression data
from the 4D Nucleome (4DN) and Genotype-Tissue Expression (GTEx) programs in the following aims: 1)
Determine the 3D genome architecture of Atypical teratoid/rhabdoid tumor AT/RT tumors. We have initiated our
study using AT/RT, tumors thought to be due to defects in early development11 and the most common brain
tumor in children less than six months of age. 1.A. We will develop a bioinformatics pipeline that uses Akita to
quantify how much a genetic variant is predicted to disrupt 3D chromatin interactions in AT/RT tumors. 1.B. We
will validate and determine the functional relevance of 3D genomic folding disruptions observed in AT/RT tumors.
2) Determine the 3D genome architecture of malignant pediatric tumors. We will extend our analyses with Akita
to additional malignant pediatric brain tumors, focusing for this pilot project on the most malignant and treatment
refractory tumors. This innovative project, using a new deep-learning tool Akita, will lead to, novel research
hypotheses and will accelerate the discovery ...

## Key facts

- **NIH application ID:** 10585741
- **Project number:** 1R03OD034499-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Nadia Dahmane
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,151
- **Award type:** 1
- **Project period:** 2022-09-20 → 2024-09-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585741

## Citation

> US National Institutes of Health, RePORTER application 10585741, Deciphering the 3D genome of pediatric brain tumors (1R03OD034499-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10585741. Licensed CC0.

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