权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10672947
负责人：
CHRISTOPHER B UMBRICHT
金额：
$ 34.77万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10672947
关键词：
Age Assessment tool Atypia Benign Biochemical 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 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 bisulfite sequencing breast density candidate marker clinical development cohort cost detection assay electronic data follow-up genome-wide high risk population high throughput analysis hormonal signals improved malignant breast neoplasm methylome multiplex assay preventive intervention prognostic performance promoter relational database risk stratification sodium bisulfite surveillance strategy tissue fixing tool tumor progression

项目摘要

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.

项目总结