# Three-dimensional characterization of epigenomic intratumoral heterogeneity in IDH-mutant glioma

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $65,310

## Abstract

Project Summary/Abstract
The failure of cancer therapies to achieve durable responses is often attributed to intratumoral heterogeneity
(ITH), which fosters tumor evolution and the generation of therapy-resistant clones. ITH has historically been
assessed by genomic alterations such as somatic mutation and copy-number alteration. Recent studies
suggest that epigenomic ITH may also contribute to tumor evolution and therapy resistance. However, the
prevalence and degree of epigenomic ITH are not well understood. Low-grade gliomas (LGGs), which include
grade II astrocytoma and grade II oligodendroglioma, are slow-growing tumors treated with surgical resection,
and in some cases, with radiation and temozolomide chemotherapy. These tumors inevitably recur as grade III
astrocytoma and grade III oligodendroglioma, or as grade IV secondary glioblastoma. LGGs are characterized
by clonal mutations in isocitrate dehydrogenase (IDH) genes, which drive production of the oncometabolite D-
2-hydroxyglutarate (2HG) and result in epigenomic alterations including the development of the glioma CpG
island methylator phenotype (G-CIMP). Data published by our laboratory and preliminary data presented here
indicate that the epigenomes of IDH-mutant gliomas display ITH across spatially distinct tumor regions and
show evolution over time. In this proposal, we will test the central hypothesis that epigenomic ITH is a feature
of IDH-mutant gliomas that is biologically and clinically significant. For a cohort of IDH-mutant glioma patients,
we will characterize ITH in three-dimensional space using a novel topographic approach developed in
collaboration with neurosurgeons, neuropathologists, and biomedical imaging experts. We will profile DNA
methylation and chromatin accessibility, two complementary approaches towards characterizing the
epigenomic state of the cell. In Aim 1, we will investigate the spatial patterning of epigenomic ITH relative to
genomic ITH. In Aim 2, we will determine the biological significance of epigenomic ITH by investigating its
relationship with gene regulation. In Aim 3, we will determine the clinical significance of epigenomic ITH by
investigating its relationship with tumor histologic features and immune cell content, and by investigating ITH of
DNA-methylation based biomarkers including MGMT methylation and epigenetic age. Collectively, these
studies will provide the most comprehensive characterization of epigenomic ITH to date. Knowledge gained
from these studies will deepen our understanding of the contribution of epigenomic ITH to tumor evolution and
therapy resistance, ultimately guiding the design of novel and improved approaches towards countering
therapy failure. The results of this study may also directly impact clinical practice in the treatment of IDH-
mutant glioma by supporting the use of epigenomic signatures in glioma grading and diagnostics and by
guiding the use of immunotherapeutics and biomarkers for patient stratification.

## Key facts

- **NIH application ID:** 9956591
- **Project number:** 5F32CA239472-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Radhika Mathur
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956591

## Citation

> US National Institutes of Health, RePORTER application 9956591, Three-dimensional characterization of epigenomic intratumoral heterogeneity in IDH-mutant glioma (5F32CA239472-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9956591. Licensed CC0.

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