COPY NUMBER VARIANTS AND EARLY-ONSET BREAST CANCER

拷贝数变异和早发性乳腺癌

基本信息

批准号：
8328949
负责人：
Paul Joseph Goodfellow
金额：
$ 61.96万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-06 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328949
关键词：
Accounting Affect Age Alleles Attention BRCA1 gene BRCA2 gene Breast Cancer Treatment Cancer Patient Candidate Disease Gene Custom Data Detection Development Diagnosis Disease Environmental Risk Factor Family Family Study Family history of Family member Frequencies Future Genes Genetic Predisposition to Disease Genetic Risk Genetic Variation Genome Goals Hereditary Disease Hormones Inherited Learning Malignant Neoplasms Maps Methods Minor Modeling Mutation Mutation Analysis Outcome Parents Pathway interactions Play Population Predisposition Prevention strategy Research Resolution Resources Risk Role Sister TP53 gene Testing Variant Woman Work advanced disease breast cancer diagnosis breast tumorigenesis cancer risk cohort cost effective density early onset experience follow-up genetic pedigree genetic risk factor human disease interest loss of function malignant breast neoplasm member novel proband segregation tumor young woman

项目摘要

DESCRIPTION (provided by applicant): Breast cancer takes its greatest toll on young women. Young women frequently have biologically aggressive tumors. They often present with advanced disease and their tumors are frequently hormone non-responsive, thereby limiting treatment options. Young women suffer lower than average disease-free and overall survival. The work proposed is focused on discovery of the as yet unknown genetic risk factors that underlie development of early-onset breast cancer. These findings will pave the way for future studies to elucidate how genetic risk and environmental factors interact and account for the aggressive tumors and poor outcome young breast cancer patients experience. We hypothesize copy number variants (CNVs) play an important role in risk for development of early-onset breast cancer. Three inter-related aims are proposed to identify the inherited CNVs and genes they impact that are important in early-onset breast cancer. Aim 1. Assess copy number variants (CNVs) in 120 BRCA1 and BRCA2 negative breast cancer patients diagnosed <40 along with their biologic parents. We will map CNVs at high density in the genomes of 120 early-onset breast cancer patients, comparing their CNV make-up with their parents'. Aim 2. Validate CNVs and evaluate an additional cohort of early-onset breast cancer patients for variants identified in Aim 1. CNVs identified in Aim 1 will be validated using a high resolution custom array to identify candidate breast cancer susceptibility loci. A total of 240 cases will be investigated. Variant-specific PCR amplicons will be developed for a select set of CNVs. Aim 3. Characterize CNVs and candidate genes to determine their role in breast cancer risk. Mutation analysis will be our primary method for determining if a CNV-associated candidate gene is involved in breast cancer risk. Mutations seen in breast cancer cases but not in controls would be taken as evidence for a gene's role in breast cancer susceptibility. We will investigate families for co-segregation of CNVs with cancer and use family member DNAs to verify and refine interpretation of allelism for CNVs of interest.

描述（由申请人提供）：乳腺癌对年轻女性的影响最大。年轻女性经常患有生物侵袭性肿瘤。他们通常患有晚期疾病，而且他们的肿瘤通常对激素无反应，从而限制了治疗选择。年轻女性的无病生存率和总生存率低于平均水平。拟议的工作重点是发现导致早发性乳腺癌发展的迄今未知的遗传风险因素。这些发现将为未来的研究铺平道路，以阐明遗传风险和环境因素如何相互作用，并解释年轻乳腺癌患者所经历的侵袭性肿瘤和不良预后。我们假设拷贝数变异（CNV）在早发性乳腺癌的发生风险中发挥重要作用。提出了三个相互关联的目标来识别遗传性 CNV 及其影响的基因，这些对早发性乳腺癌很重要。目标 1. 评估 120 名诊断为 <40 的 BRCA1 和 BRCA2 阴性乳腺癌患者及其亲生父母的拷贝数变异 (CNV)。我们将在 120 名早发乳腺癌患者的基因组中高密度地绘制 CNV 图谱，并将他们的 CNV 组成与其父母的进行比较。目标 2. 验证 CNV 并评估另一组早发乳腺癌患者的目标 1 中确定的变异。目标 1 中确定的 CNV 将使用高分辨率定制阵列进行验证，以确定候选乳腺癌易感位点。总共将调查240起案件。将为一组选定的 CNV 开发变体特异性 PCR 扩增子。目标 3. 表征 CNV 和候选基因，以确定它们在乳腺癌风险中的作用。突变分析将是我们确定 CNV 相关候选基因是否与乳腺癌风险有关的主要方法。在乳腺癌病例中观察到但在对照中未观察到的突变将被视为基因在乳腺癌易感性中所起作用的证据。我们将调查 CNV 与癌症的共分离家族，并使用家族成员 DNA 来验证和完善对感兴趣的 CNV 等位性的解释。