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

项目摘要 乳腺癌是全世界女性中最常见的癌症，乳腺癌的发病率 在过去的三十年里，年增长率为3.1%。虽然乳房X光检查可能会及早发现乳腺癌， 它的应用 往往受到过度诊断和成本增加的限制。为了克服这些限制，风险预测 和人群分层，以确定可能从乳腺癌乳房X光检查中受益的女性 放映。因此， 确定敏感但稳健的生物相关风险标记，用于风险预测和 人口分层是最终减轻乳腺癌疾病负担的迫切需要。完整的DNA 乳房组织的修复是必不可少的，因为在女性一生中，乳房组织会发生广泛的重塑。 实验证据为同源重组修复(HRR)这一主要的DNA修复提供了强有力的支持 负责修复DNA双链断裂的途径，以防止乳腺细胞肿瘤的发生。 一个经典的例子是主要的高和中等外显性乳腺癌易感基因(例如，BRCA1， BRCA2、CHEK2、ATM、PALB2和RAD51D)是HRR中的关键角色。因此，次优的HRR容量可能 导致DNA损伤增加，患乳腺癌的风险增加。然而，由于 缺乏无创测量HRR能力的工具，这种假设尚未在非家族性或 未选择的设置。最近，我们开发了一种表型分析来测量外周血中的hrr能力。 淋巴细胞(PBL)。我们的检测可以为代孕的多步骤HRR的效率提供读数 组织，这是种群研究的关键。在我们初步的乳腺癌研究中，我们发现 病例组的人力资源容量显著低于对照组(P&lt；0.001)，且降低的人力资源容量 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 利用前列腺癌、肺癌、结直肠癌和乳腺癌的丰富资源 卵巢癌筛查试验(PLCO)队列。我们将首先进行一项嵌套病例对照研究来验证 PBL中HRR能力作为乳腺癌总体和亚型的危险因素。然后，我们将对影响进行评估 外周血淋巴细胞次优HRR在乳腺肿瘤发生中的作用 评估 PBL中次优的HRR容量作为 乳腺肿瘤中HRR突变特征的预测生物标记物。以前的研究表明，HRR 肿瘤的缺陷有遗传决定因素。然而，PBL中的HRR是否与HRR相关 乳腺肿瘤组织的表型尚不清楚。最后，为了剖析PBL中HRR的遗传决定因素，我们 将制定PBL中HRR能力的多基因风险评分(PR)，并进一步评估 利用现有的大规模遗传和基因组研究具有乳腺癌风险和肿瘤突变特征的PR 数据集。

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.