# High-throughput Epigenomic Mapping of Regulatory Elements in Ovarian Cancer at Basepair Resolution

> **NIH NIH R37** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $623,158

## Abstract

PROJECT SUMMARY / ABSTRACT
 Epithelial ovarian cancer (OC) is the deadliest gynecological cancer in the US. It consists of several
histotypes, each biologically distinct with different clinical challenges. Clear cell OC (CCOC) represents a much
understudied histotype marked by low response rates to standard chemotherapies and a lack of effective
therapeutic options. Endometrioid OC (ENOC) is a closely related histotype. CCOC and ENOC share a common
tissue of origin (endometriosis) and key genetic mutations but differ markedly in their clinical behavior. Our
recently published study showed that most of these mutations were detectable in untransformed endometriosis,
suggesting further distinct mechanisms of malignant transformation. We seek to delineate the contributions of
altered epigenetics and transcriptional control in this process. The most prevalent histotype, high grade serous
OC (HGSOC) harbors epigenetic inactivation of key tumor suppressor genes BRCA1 and RAD51C in the
homologous DNA repair (HR) pathway, a pathway highlighted for its therapeutic relevance. These tumors often
recur within five years despite initial good response to platinum therapy. Past epigenetic studies of primary OC
have usually been conducted without stratification of histotypes, or heavily biased towards the most common
histotype HGSOC. Even for HGSOC, epigenetic profiling has been performed with only limited genome coverage,
focused primarily on gene promoters. Enhancers have incurred much interest in recent literature as the most
dynamically used compartment of the genome, but enhancer studies of primary human OC samples, especially
those of distinct histotypes, are generally lacking. This is attributable in part to limitations of existing technology.
To address this knowledge gap, we propose to implement an innovative cost-effective tool, compatible with
primary human samples, to profile enhancers and other regulatory elements using a targeted technology that
jointly profiles DNA methylation and nucleosome occupancy (Target-NOMe Seq). We will also develop the
associated bioinformatic pipeline needed to apply this technology (Aim 1). We will use Target-NOMe Seq and
transcriptome profiling to analyze 300 bulk OC tumor samples, as well as microdissected tumor and supportive
stromal compartments on a subset of samples (Aim 2). With this rich dataset we hope to address the research
and clinical questions described above (Aim 3). We will use enhancer and promoter epigenetic states, and a
new category of non-coding RNA - enhancer RNA (eRNA), as well as the expression levels of transcription
factors and candidate target genes to define transcriptional regulatory networks. By analyzing which networks
are altered in the different histotypes, we will gain a better understanding of the distinct molecular makeup of
each of these histotypes. The relatively high sequencing depth of our focused Target-NOMe Seq technology will
also allow us to assess intertumor and subclonal hete...

## Key facts

- **NIH application ID:** 9963158
- **Project number:** 5R37CA230748-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Hui Shen
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $623,158
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963158

## Citation

> US National Institutes of Health, RePORTER application 9963158, High-throughput Epigenomic Mapping of Regulatory Elements in Ovarian Cancer at Basepair Resolution (5R37CA230748-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963158. Licensed CC0.

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