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

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.