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: 10475413
• 负责人: Song Liu
• 金额: $ 51.23万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 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 2023-06-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475413
• 关键词: BRCA1 gene; BRCA2 gene; Biological Assay; 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; Diagnostic; Etiology; Frequencies; Genetic; Genetic Determinism; Genotype; Goals; High Risk Woman; Immunophenotyping; Incidence; Individual; Intervention; Investigation; Lead; 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 乳腺癌是全球女性中最常见的癌症，因为乳腺癌的发生率 在过去的三十年中，每年增加3.1％。尽管乳房X线摄影可能会尽早检测到乳腺癌，但 它的应用 通常受到过度诊断和成本增加的限制。为了克服限制，风险预测 需要种群分层以识别可能受益于乳腺癌乳房X线摄影的女性 筛选。因此， 确定风险预测的敏感但强大的生物学风险标志物 人口分层是最终减轻乳腺癌疾病负担的压力。完整的DNA 由于整个女性一生的组织进行了大量重塑，因此在乳房组织中维修至关重要。 实验证据为同源重组修复（HRR）提供了强有力的支持，这是一种主要的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，主要的高和中度渗透率乳腺癌易感基因（例如，BRCA1， BRCA2，CHEK2，ATM，PALB2和RAD51D）是HRR的关键参与者。因此，次优的HRR容量可能 导致DNA损伤的积累增加和乳腺癌的风险升高。但是，由于 缺乏测量HRR容量非侵入性的工具，这种假设尚未在非家庭或 未选择的设置。最近，我们开发了一种表型测定，以测量外周血的HRR能力 淋巴细胞（PBL）。我们的测定可以读取HRR在代理中多个步骤的效率 组织，人口研究至关重要。在我们的初步乳腺癌研究中，我们发现 病例的HRR容量明显低于对照组（P <0.001），HRR容量降低为 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 通过利用前列腺，肺，结肠直肠和 卵巢癌筛查试验（PLCO）队列。我们将首先进行嵌套的病例对照研究以验证 PBL中的HRR容量是总体和亚型的乳腺癌危险因素。然后，我们将评估影响 PBL中的次优HRR在乳腺肿瘤发生上 评估 PBL中的次优HRR作为一个 乳腺肿瘤中HRR突变特征的预测生物标志物。如先前的研究，HRR 肿瘤缺乏具有遗传决定因素。但是，PBL中的HRR是否与HRR相关 乳腺肿瘤组织中的表型尚不清楚。最后，要剖析PBL中HRR的遗传决定因素，我们 将在PBL中为HRR容量开发多基因风险评分（PRS），并进一步评估 使用现有的大规模遗传和基因组的乳腺癌风险和肿瘤突变签名的PR 数据集。