Discovery and validation of early molecular breast cancer risk markers in benign breast disease

良性乳腺疾病中早期分子乳腺癌风险标记的发现和验证

• 批准号: 10245259
• 负责人: CHRISTOPHER B UMBRICHT
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245259
• 关键词: Age; Archives; Assessment tool; Atypia; Benign; Biochemical Markers; Biological Assay; Biological Markers; Biopsy; Body mass index; Breast; Breast Cancer Detection; Breast Cancer Risk Factor; Breast Diseases; Breast biopsy; Case-Control Studies; Clinical; Complement; Copy Number Polymorphism; DNA; DNA Methylation; DNA copy number; Data; Databases; Deltastab; Development; Disease; Epigenetic Process; Estrogen Receptor Status; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen receptor positive; Etiology; Event; Family; Fine needle aspiration biopsy; Formalin; Future; Genetic Predisposition to Disease; Genome; Genomics; Goals; High Risk Woman; Hormone Receptor; Hormones; Hyperplasia; Immunohistochemistry; Individual; Institution; Lesion; Liquid substance; Malignant Neoplasms; Mammary Gland Parenchyma; Mammographic Density; Mammography; Measurable; Methylation; Minority; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Nipples; Outcome; Pathologic; Patients; Performance; Pilot Projects; Population; Prevention strategy; Recording of previous events; Relative Risks; Resolution; Resources; Risk; Risk Assessment; Risk Factors; Risk Marker; Role; Sampling; Sensitivity and Specificity; Statistical Models; Terminal Ductal Lobular Unit; Testing; Tissue Sample; Tissues; Training; United States; Validation; Woman; assay development; base; bisulfite sequencing; breast density; candidate marker; clinical development; cohort; cost; electronic data; follow-up; genome-wide; high risk population; high throughput analysis; hormonal signals; malignant breast neoplasm; methylome; multiplex assay; preventive intervention; prognostic performance; promoter; relational database; risk stratification; sample archive; sodium bisulfite; surveillance strategy; tissue archive; tool; tumor progression

PROJECT SUMMARY 1.6 million women undergo breast biopsy for benign breast disease (BBD) annually in the United States. 90% of these show no evidence of cellular atypia, and are at only modestly increased risk for breast cancer, but this group represents the great majority who develop cancer among women with BBD, since women with identifiable risk factors, such as atypia or strongly positive family history are a small minority. BBD lesions in women who later progress to cancer very likely display molecular changes which predate overt cancer by years. An assay detecting such changes will provide a critical improvement in our ability accurately identify high risk women for preventive interventions (particularly if it distinguishes risk of estrogen receptor (ER) positive vs. negative breast cancer), and allow better targeting advanced surveillance strategies to women who will benefit the most. Aberrant promoter methylation has been documented very early in cancer progression. We have successfully adapted genome-wide array-based tools interrogating the methylome to formalin-fixed tissue samples, creating an opportunity to study archival samples with known long-term outcomes. For the past 15 years, we have built an integrated clinical-pathological relational database of all electronic data of over 75,000 breast patients at this institution since 1985. We identified women with non-atypical BBD who subsequently developed breast cancer (cases), and matched them to women with BBD who remained cancer- free (controls) with documented follow-up of a minimum of 10 years. In a pilot study, we demonstrated that molecular signatures in archival BBD tissue matched signatures present in subsequent invasive breast cancer (IBC); furthermore, these signatures were distinct from those in control BBD patients with no evidence of subsequent IBC, and differed in ER+ vs ER- cases. We now propose to combine our scientific and clinical resources to enable the discovery and validation of risk markers derived from BBD. We have identified over 500 cases with BBD predating IBC and paired IBC samples with known ER status with available archival tissue blocks. We will perform a case-control study of the methylomes of archival non-atypical non-familial BBD from 185 cases as well as their subsequent IBC, and 75 control samples, matched by follow-up, age and presence of hyperplasia. We will also capture known risk factors for IBC, mammographic density and body mass index, assess involution of terminal duct lobular units (TDLU), and characterize the status of key hormone receptors by semiquantitative immunohistochemistry. Our hypothesis is that molecular changes are present in BBD prior to the development of IBC, and are distinct in women who subsequently develop ER + versus ER- IBC. Our overarching goal is the identification of molecular changes in breast tissue that will allow the accurate risk stratification of all women undergoing breast biopsy showing no atypia. In the future, such biomarkers may be applicable to minimal samples of breast tissue such as those obtained with random fine needle aspiration or in nipple fluid.

项目概要 在美国，每年有 160 万名女性因良性乳腺疾病 (BBD) 接受乳腺活检。 90% 其中没有显示出细胞异型性的证据，并且仅适度增加患乳腺癌的风险，但这 该群体代表了患有 BBD 的女性中患癌症的绝大多数，因为患有 BBD 的女性 可识别的危险因素，如异型性或强阳性家族史只占少数。 BBD 病变 后来发展为癌症的女性很可能表现出早于明显癌症的分子变化 年。检测此类变化的检测将为我们准确识别的能力提供关键改进 高风险女性进行预防性干预（特别是如果它区分雌激素受体（ER）的风险 阳性与阴性乳腺癌），并允许更好地针对以下女性制定高级监测策略： 将受益最多。异常的启动子甲基化在癌症进展的早期就已被记录。 我们已经成功地采用了基于全基因组阵列的工具来询问福尔马林固定的甲基化组 组织样本，创造了一个研究具有已知长期结果的档案样本的机会。 15年来，我们建立了所有电子数据的综合临床病理关系数据库 自 1985 年以来，该机构对超过 75,000 名乳腺患者进行了调查。我们发现患有非典型 BBD 的女性 随后患上乳腺癌（病例），并将其与患有 BBD 但仍处于癌症状态的女性进行匹配- 免费（对照）并记录至少 10 年的随访。在一项试点研究中，我们证明了 档案 BBD 组织中的分子特征与随后浸润性乳腺癌中存在的特征相匹配 （国际散装公司）；此外，这些特征与对照 BBD 患者的特征不同，没有证据表明 随后的 IBC，并且 ER+ 与 ER- 病例有所不同。 我们现在建议结合我们的科学和临床资源来发现和验证风险 源自 BBD 的标记。我们已发现 500 多例 BBD 早于 IBC 和配对 IBC 的病例 具有已知 ER 状态的样本以及可用的存档组织块。我们将进行病例对照研究 来自 185 个病例的档案非非典型非家族性 BBD 及其随后的 IBC 的甲基化组，以及 75 对照样本，与随访、年龄和是否存在增生相匹配。我们还将捕获已知风险 IBC、乳房X光密度和体重指数的因素，评估终末导管小叶单位的退化 （TDLU），并通过半定量免疫组织化学表征关键激素受体的状态。 我们的假设是，在 IBC 发展之前，BBD 中就存在分子变化，并且是截然不同的 随后发生 ER + 的女性与 ER- IBC 的比较。我们的首要目标是确定 乳腺组织的分子变化将有助于对所有接受乳腺手术的女性进行准确的风险分层 活检显示无异型性。将来，此类生物标志物可能适用于最少的乳房样本 组织，例如通过随机细针抽吸或乳头液中获得的组织。