# Homologous recombination repair capacity in peripheral blood lymphocytes as a breast cancer risk factor

> **NIH NIH U01** · UNIVERSITY OF VIRGINIA · 2024 · $484,154

## Abstract

Project Abstract
Breast cancer is the most common cancer among women worldwide, as the incidence of breast cancer has
increased annually by 3.1% over the past three decades. Though mammography may detect breast cancer early,
its application
is often limited by overdiagnosis and increased cost. To overcome the limitations, risk prediction
and population stratification are needed to identify women likely to benefit from breast cancer mammography
screening. Thus,
identifying sensitive yet robust biologically relevant risk markers for risk prediction and
population stratification is a pressing need to ultimately reduce breast cancer disease burden. An intact DNA
repair is essential in breast tissue due to the extensive remodeling of the tissue throughout a woman's life.
Experimental evidence provides strong support for homologous recombination repair (HRR), a major DNA repair
pathway responsible for repairing DNA double-strand breaks, in guarding against mammary cell tumorigenesis.
A classic example is that major high- and moderate-penetrance breast cancer susceptibility genes (e.g., BRCA1,
BRCA2, CHEK2, ATM, PALB2, and RAD51D) are key players in HRR. Therefore, suboptimal HRR capacity may
lead to an increased accumulation of DNA damage and an elevated risk of breast cancer. However, due to the
lack of tools to measure HRR capacity non-invasive, such assumption has not been tested in the non-familial or
unselected setting. Recently, we developed a phenotypic assay to measure HRR capacity in peripheral blood
lymphocytes (PBLs). Our assay can provide a readout of the efficiency of the multiple steps of HRR in surrogate
tissue, which is critically needed for population studies. In our preliminary breast cancer study, we found that
HRR capacity was significantly lower in cases than in controls (P<0.001), and decreased HRR capacity was
associated with an increased risk of breast cancer. Our primary goal is to fully assess the role of HRR in PBLs
in breast cancer development by taking advantage of the rich resources from the Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial (PLCO) cohort. We will first carry out a nested case-control study to validate
HRR capacity in PBLs as a breast cancer risk factor overall and by subtypes. Then, we will evaluate the impact
of suboptimal HRR in PBLs on breast tumorigenesis by
evaluating
suboptimal HRR capacity in PBLs as a
predictive biomarker for the mutational signature of HRR in breast tumors. As shown in previous studies, HRR
deficiency in tumors has genetic determinants. However, whether HRR in PBLs is correlated with HRR
phenotype in breast tumor tissue is unknown. Lastly, to dissect the genetic determinants of HRR in PBLs, we
will develop a polygenetic risk score (PRS) for HRR capacity in PBLs and further assess the association of the
PRS with breast cancer risk and tumor mutational signature utilizing existing large-scale genetic and genomic
datasets.

## Key facts

- **NIH application ID:** 10909392
- **Project number:** 5U01CA260731-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Song Liu
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,154
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909392

## Citation

> US National Institutes of Health, RePORTER application 10909392, Homologous recombination repair capacity in peripheral blood lymphocytes as a breast cancer risk factor (5U01CA260731-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909392. Licensed CC0.

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