COPY NUMBER VARIANTS AND EARLY-ONSET BREAST CANCER

描述(申请人提供)：乳腺癌对年轻女性的危害最大。年轻女性经常患有具有生物侵袭性的肿瘤。他们经常出现晚期疾病，他们的肿瘤经常是激素无反应的，从而限制了治疗选择。年轻女性的无病存活率和总体存活率低于平均水平。建议的工作重点是发现导致早发性乳腺癌发生的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病风险中起重要作用。提出了三个相互关联的目标来确定遗传的CNV及其影响的基因，这些基因在早发性乳腺癌中是重要的。目的1.评估120例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名早发性乳腺癌患者的基因组中绘制高密度的CNV图谱，比较他们与父母的CNV构成。目的2.验证CNV并评估另一个早发性乳腺癌患者队列中AIM 1中确定的变异。将使用高分辨率定制阵列来验证AIM 1中确定的CNV，以确定候选乳腺癌易感基因。共将调查240起案件。将为一组精选的CNV开发变种特异性的PCR扩增片段。目的3.确定CNV和候选基因的特征，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。在乳腺癌病例中发现的突变，而在对照组中没有发现的突变，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与癌症共分离的家系，并使用家庭成员DNA来验证和完善感兴趣CNV的等位基因解释。

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.