# Landscape and characterization of promoter mutations driving triple-negative breast cancer

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $188,038

## Abstract

PROJECT SUMMARY
Triple-negative breast cancer (TNBC) is traditionally associated with fewer identified genetic changes than other
subtypes, precluding therapies that target tumor-specific dependencies such as HER2 or ER. However, both
germline and somatic loss of homologous recombination (HR)-mediated DNA repair is a hallmark driver of TNBC.
Compared to HR repair deficiency (HRD) TNBC from white women in which genetic drivers are common, those
from women of African ancestry tend to be enriched for epigenetic silencing of HRD gene promoters through
DNA methylation. TNBCs with either genetic or epigenetic HRD are susceptible to PARP inhibitor therapy.
Unfortunately, only a fraction of HRD tumors have an identifiable genetic or epigenetic alteration, potentially
leading to missed opportunities for patients who would benefit from HRD-targeted treatment.
Epigenetic silencing of HRD gene promoters in women of African ancestry suggests that somatic alterations of
promoters could also cause HRD. However, we know very little about recurrent, functional promoter mutations
in breast cancer. This is partially caused by incomplete genomic sequencing at promoter regions due to technical
challenges in existing datasets. We have recently developed a targeted assay to deeply sequence the promoters
of >3,000 cancer gene promoters. With our innovative and unique technology at hand, we are ready to address
the central hypothesis that TNBC from women of African ancestry harbor actionable genetic driver
alterations in cancer gene promoters that induce HRD or other therapeutically relevant phenotypes. We
plan to test our hypothesis by (i) profiling ~120 TNBCs and matched normal samples from a diverse patient
population with our technology to identify candidate driver somatic mutation in promoters of HRD and other
cancer genes; (ii) associate these mutations with matched gene expression, treatment response and clinical
outcome; and (iii) pilot a functional evaluation strategy by characterizing events in the TP53 5’ region in relevant
cell line models. Our research carries the potential to identify novel genetic promoter alterations in HRD and
potentially other cancer genes in patients from diverse ancestries with aggressive TNBC. If successful, this pilot
project (i) can be scaled to investigate larger patient cohorts to discover promoter-associated driver events; and
(ii) has the multidisciplinary study team to translate potential findings into clinically relevant biomarkers for HRD-
targeted treatment in the future.

## Key facts

- **NIH application ID:** 10887645
- **Project number:** 5R21CA284602-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** LEIF W ELLISEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $188,038
- **Award type:** 5
- **Project period:** 2023-07-13 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887645

## Citation

> US National Institutes of Health, RePORTER application 10887645, Landscape and characterization of promoter mutations driving triple-negative breast cancer (5R21CA284602-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10887645. Licensed CC0.

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