# Elucidating Mechanisms of Loss of Heterozygosity in Diploid Cells

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $46,752

## Abstract

Project Summary Abstract
Loss of heterozygosity (LOH) is the loss of the functional copy of a tumor suppressor gene in
heterozygous individuals, leaving only the mutant copy, thereby contributing to cancer initiation
and progression. Understanding how LOH arises in healthy cells is a vital component of cancer
research, as it could lead to opportunities to prevent cancer in patients with increased early
screening for individuals with mutations putting them at high risk for LOH, or with identification
and targeting of cells that have undergone dangerous LOH. LOH can develop through deletions
of whole chromosome arms or smaller regions of the genome, nondisjunction incidents, or
homologous recombination events between homologous chromosomes (i.e., interhomolog
homologous recombination, IH-HR). Despite decades of research, a critical need remains to
identify the causes of LOH in normal or precancerous cells. Detecting these mechanisms in
already established tumors is often difficult due to high levels of aneuploidy, ongoing
chromosome instability, and DNA damage. We have recently developed a high throughput flow
cytometry-based system which is sensitive for detecting LOH in normal diploid cells. Our
objective is to exploit this system to identify and quantify mechanisms of LOH that arise from
DNA double-strand breaks (DSBs), and the factors that modulate these events. We hypothesize
that mechanisms of LOH which occur as a result of DSBs include copy number neutral LOH, as
from IH-HR or non-disjunction associated with chromosome duplication and furthermore, that
these events are modulated by the location of the DSB and DNA repair proteins, including
proteins that act on recombination intermediates. We will address this hypothesis through the
following specific aims: In Aim 1, we will investigate how proteins that act on recombination
intermediates impact LOH arising from IH-HR, utilizing our flow-cytometry based system. We
will assay the frequency of LOH that arises from IH-HR in the presence or absence of proteins
that both prevent and contribute to crossover events, which can lead to long-range LOH. In Aim
2, we will take an unbiased approach to explore additional mechanisms of LOH arising from a
DSB. We will determine how LOH mechanism is affected by the location of a DSB along a
chromosome and by loss of different DSB repair pathways. This work will allow us to identify the
factors that can contribute to or even prevent LOH, and give a better understanding of how
these initiating events in cancer occur.

## Key facts

- **NIH application ID:** 10387419
- **Project number:** 1F31CA268775-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Samantha Brooke Regan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-06-22 → 2025-06-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387419

## Citation

> US National Institutes of Health, RePORTER application 10387419, Elucidating Mechanisms of Loss of Heterozygosity in Diploid Cells (1F31CA268775-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10387419. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*