A novel model system for risk assessment of BRCA carriers

一种新的 BRCA 携带者风险评估模型系统

基本信息

批准号：
8548094
负责人：
Rory Landon Cochran
金额：
$ 4.22万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-30 至 2014-08-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8548094
关键词：
Accounting Address Adverse effects Alleles BRCA1 gene BRCA2 gene Benefits and Risks Benign Biological Assay Biological Models Breast Cancer-Predisposing Gene Cataloging Catalogs Cell Cycle Checkpoint Cell Line Chemopreventive Agent Clinical DNA DNA Damage DNA Repair DNA Sequence Data Databases Decision Making Defect Disease Double Strand Break Repair Effectiveness Engineering Environmental Risk Factor Epithelial Cells Family Fluorescent in Situ Hybridization Gene Targeting Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic screening method Genome Genomic Instability Genomics Genotype Germ-Line Mutation Goals Human In Vitro Individual Inherited Knock-in Mouse Knock-out Knowledge Lead Link Malignant Neoplasms Malignant neoplasm of ovary Mammary gland Mastectomy Measures Mediating Methods Modeling Mutagens Mutate Mutation Operative Surgical Procedures Patients Penetrance Phase Phenotype Poly(ADP-ribose) Polymerases Population Predisposition Prevention strategy Primary Prevention Procedures Radiation Relative Risks Reporting Risk Risk Assessment Role Salpingo-Oophorectomy Sampling Single Nucleotide Polymorphism Somatic Cell Stratification System Techniques Technology Testing Uncertainty United States Up-Regulation Variant base cancer prevention cancer risk carcinogenesis effective therapy high risk homologous recombination inhibitor/antagonist lifetime risk malignant breast neoplasm mutant novel prophylactic response tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): With recent advances in DNA sequencing technology, profiling one's own genetic information is becoming a reality for many patients and their families. In fact, assaying for mutated genes known to increase the risk of breast cancer has become commonplace for individuals at high risk. Hereditary forms of breast cancer comprise approximately 20,000 cases annually in the United States. It is believed that the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, account for the majority of germ-line mutations in families with a genetic predisposition for developing breast and/or ovarian cancers. Since their discovery in the mid 1990's, over a thousand different alleles have been associated with each gene and these DNA germline mutations have been catalogued in the Breast Cancer Database. Unfortunately, a large number of germline changes reported for either BRCA1 or BRCA2 are not definitively linked to disease. These genomic alterations have been termed variants of uncertain significance (VUS) and their role in breast carcinogenesis remains unclear. In addition, penetrance of known deleterious mutations varies widely among carriers and it is hypothesized this is due to both genetic and environmental modifiers. This variability creates important clinical challenges in assessing carrier risk, since many individuals elect for prophylactic procedures or chemopreventive measures that are expensive and associated with significant side effects. Using modern somatic cell gene targeting techniques, we are developing a novel model to assess relative risk for deleterious BRCA alleles. In addition, we will use this model to further categorize VUS as either benign or deleterious. By thoroughly characterizing BRCA alleles, we hope to provide additional knowledge for further risk stratification that could be incorporated with many current models. This will aid clinicians and families that harbor these mutations/VUS in making decisions when considering the risks and benefits of prophylactic surgeries and other primary prevention strategies.

描述（由申请人提供）：随着DNA测序技术的最新进展，对自己的遗传信息进行了分析，对许多患者及其家人来说正在成为现实。实际上，对于已知增加乳腺癌风险的突变基因的测定对于处于高风险的个体而言已成为司空见惯。遗传形式的乳腺癌每年在美国约有20,000例病例。据认为，乳腺癌和卵巢癌易感性基因BRCA1和BRCA2是遗传性易感性乳腺癌和/或卵巢癌的家族中的大部分种系突变。自1990年代中期发现它们以来，每个基因都与一千多种不同的等位基因相关联，并且这些DNA种系突变已在乳腺癌数据库中分类。不幸的是，报告的BRCA1或BRCA2报告的种系变化与疾病无关紧要。这些基因组改变被称为不确定意义（VU）的变异，它们在乳腺癌发生中的作用尚不清楚。另外，已知有害突变的外观在载体中有很大变化，这是由于遗传和环境修饰剂构成的。这种可变性在评估载体风险方面引起了重要的临床挑战，因为许多人选择昂贵且与重大副作用相关的预防程序或化学预防措施。使用现代体细胞基因靶向技术，我们正在开发一种新型模型，以评估有害BRCA等位基因的相对风险。此外，我们将使用此模型将VUS进一步归类为良性或有害的。通过彻底表征BRCA等位基因，我们希望为进一步的风险分层提供更多知识，这些知识可以与许多当前模型合并。这将有助于携带这些突变/VU的临床医生和家庭在考虑预防手术的风险和益处和其他主要预防策略时做出决策。