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

外周血淋巴细胞同源重组修复能力作为乳腺癌危险因素

• 批准号: 10901445
• 负责人: Song Liu
• 金额: $ 52.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10901445
• 关键词: BRCA1 gene; BRCA2 gene; Biological Assay; Breast Cancer Early Detection; Breast Cancer Patient; Breast Cancer Risk Factor; CHEK2 gene; Cancer-Predisposing Gene; Case/Control Studies; Cells; Characteristics; Companions; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Data; Development; Diagnosis; Diagnostic; Etiology; Frequencies; Genetic; Genetic Determinism; Genotype; Goals; High Risk Woman; Immunophenotyping; Incidence; Individual; Intervention; Investigation; Life; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammographic screening; Mammography; Measures; Modeling; Molecular; Mutation; Nested Case-Control Study; PALB2 gene; Pathway interactions; Penetrance; Peripheral Blood Lymphocyte; Phenotype; Population Study; Prevention strategy; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Resources; Risk; Risk Marker; Role; Sampling; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Tumor Tissue; Woman; biobank; breast tumorigenesis; burden of illness; cancer subtypes; cohort; cost; exome sequencing; genome-wide; genomic data; homologous recombination; individualized prevention; innovation; insight; malignant breast neoplasm; mammary; novel; polygenic risk score; population stratification; predictive marker; prospective; recombinational repair; risk prediction; risk stratification; screening; tool; tumor; tumorigenesis

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.

项目摘要 乳腺癌是全世界妇女中最常见的癌症，因为乳腺癌的发病率已 在过去的三十年里，每年增长3.1%。虽然乳房X光检查可以早期发现乳腺癌， 的应用 通常受到过度诊断和成本增加的限制。为了克服局限性，风险预测 和人群分层，以确定妇女可能受益于乳腺癌乳房X光检查 筛选因此，在本发明中， 识别用于风险预测的敏感但稳健的生物学相关风险标志物， 人口分层是最终减少乳腺癌疾病负担的迫切需要。一个完整的DNA 修复在乳房组织中是必不可少的，这是由于在女性的一生中组织的广泛重塑。 实验证据为同源重组修复（HRR）提供了强有力的支持，HRR是一种主要的DNA修复 负责修复DNA双链断裂的途径，以防止乳腺细胞肿瘤发生。 一个经典的例子是，主要的高和中度转移率乳腺癌易感基因（例如，BRCA1， BRCA 2、CHEK 2、ATM、PALB 2和RAD 51 D）是HRR的关键参与者。因此，次优的HRR容量可能 导致DNA损伤累积增加和乳腺癌风险增加。但由于 缺乏工具来衡量HRR能力的非侵入性，这种假设尚未在非家族性或 开始设置。最近，我们开发了一种表型测定来测量外周血中HRR的能力 淋巴细胞（PBL）。我们的测定可以提供HRR在替代中的多个步骤的效率的读数。 组织，这是人口研究所急需的。在我们对乳腺癌的初步研究中，我们发现， 病例组HRR容量显著低于对照组（P<0.001）， 与乳腺癌风险增加有关。我们的主要目标是充分评估HRR在PBL中的作用 在乳腺癌的发展，利用丰富的资源，从前列腺，肺，结直肠， 卵巢癌筛查试验（PLCO）队列。我们将首先进行巢式病例对照研究， PBL中的HRR能力作为乳腺癌风险因素的总体和亚型。然后，我们将评估影响 PBL中次优HRR对乳腺肿瘤发生的影响 评价 PBL中的次优HRR能力， 乳腺肿瘤中HRR突变特征的预测生物标志物。在以往的研究中，HRR 肿瘤中的缺陷具有遗传决定因素。然而，PBL的HRR是否与HRR相关， 乳腺肿瘤组织中的表型是未知的。最后，为了剖析PBL中HRR的遗传决定因素，我们 将为PBL的HRR能力开发多基因风险评分（PRS），并进一步评估 利用现有的大规模遗传和基因组研究， 数据集。