# Discovery of Somatic Noncoding Variants that Serve as Drivers in Pediatric Cancers

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $564,115

## Abstract

PROJECT SUMMARY / ABSTRACT
Mapping of cis-regulatory elements by ENCODE and Roadmap Epigenomics has led to increased recognition of
the importance of non-coding regulatory regions, as the target for next great discovery of important somatic
variants in childhood cancers. Recent discoveries of somatic non-coding mutations that cause oncogenic
activation of TERT in melanoma and TAL1 in pediatric T-ALL support this idea, and have inspired genome-wide
investigations of non-coding somatic mutations in cancer. However, the noncoding genome is vast and largely
uncharted and it has proven difficult to distinguish the “oncogenic drivers” from the “passengers” among the
many non-coding sequence variants. By combining our computational expertise in genomic analysis with the
experimental expertise of our co-investigators Drs. Thomas Look and Suzanne Baker in molecular oncogenesis
and Dr. Chunliang Li in novel assay development, we aim to discover new somatic non-coding variants that serve
as drivers of pediatric cancer. This effort capitalizes on the strength of our work to-date on the pediatric cancer
genome landscape, including non-coding regions, and the richness of our unique resource of “omics” results
from existing whole genome sequencing (WGS) and RNA-seq of >2,000 paired tumor/normal childhood cancer
samples. Through a pilot study of 33 T-lineage acute lymphoblastic leukemia, we demonstrate that by an
integrative approach we are able to successfully distinguish “driver-mutations” from “passengers” and discover
novel variants in the non-coding genomes of childhood cancers. In Aim 1, we will discover somatic alterations
in non-coding regions that are associated with aberrant, allele-specific expression by analyzing WGS and RNA-
seq data from 2,000 patient samples and from established cancer cell lines. We will focus on sequence
alterations that form locus-specific transcription factor binding sites and employ a massively parallel reporter
assay to measure the enhancer activity of the candidate non-coding mutations. In Aim 2, we will develop a
computational framework for predicting non-coding variant pathogenicity based on statistical analysis of patient
data and mechanism studies underlying regulatory non-coding variants unveiled by laboratory investigation. We
will discover abnormal enhancer-promoter interactions in pediatric cancer patient derived xenograft (PDX)
models or cell lines using 3-D chromatin assays such as Capture-C. We will use ChIP-seq and RNA-seq to
analyze the functional consequences of non-coding variants in PDXs or cancer cell lines. In parallel we will use
CRISPR-Cas9 genome editing tools to modify or alter the mutant allele to further explore the regulation
mechanisms. In Aim 3, we will develop a web-based and user-friendly visualization tool to accelerate discovery
of non-coding driver mutations by making the non-coding variants discovered in our study publicly accessible
with an integrated genome-wide view of “omics” datasets fo...

## Key facts

- **NIH application ID:** 10148693
- **Project number:** 5R01CA216391-04
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Jinghui Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $564,115
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148693

## Citation

> US National Institutes of Health, RePORTER application 10148693, Discovery of Somatic Noncoding Variants that Serve as Drivers in Pediatric Cancers (5R01CA216391-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148693. Licensed CC0.

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