COPY NUMBER VARIANTS AND EARLY-ONSET BREAST CANCER

描述（由申请人提供）：乳腺癌对年轻女性的危害最大。年轻女性经常患有生物侵袭性肿瘤。他们经常出现疾病晚期，他们的肿瘤往往是激素无反应，从而限制了治疗选择。年轻妇女的无病生存率和总体生存率低于平均水平。这项工作的重点是发现尚不清楚的导致早发性乳腺癌的遗传风险因素。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（CNVs）在早发性乳腺癌的发展风险中起重要作用。提出了三个相互关联的目标，以确定在早发性乳腺癌中重要的遗传CNVs及其影响的基因。目的1。评估120例诊断为<40的BRCA1和BRCA2阴性乳腺癌患者及其亲生父母的拷贝数变异（CNVs）我们将在120例早发性乳腺癌患者的基因组中高密度绘制CNV图谱，并将其与父母的CNV组成进行比较。目标2。验证CNVs并评估另一组早发性乳腺癌患者在Aim 1中发现的变异。在Aim 1中发现的CNVs将使用高分辨率自定义阵列进行验证，以确定候选乳腺癌易感位点。总共将调查240个病例。变异特异性PCR扩增子将用于一组选择的CNVs。目标3。表征CNVs和候选基因以确定其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相关的主要方法。在乳腺癌病例中发现的突变，而在对照组中没有发现，可以作为基因在乳腺癌易感性中所起作用的证据。我们将研究CNVs与癌症的家族共分离，并使用家族成员dna来验证和完善对感兴趣的CNVs的等位基因的解释。

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. PUBLIC HEALTH RELEVANCE: The potential impact for the work proposed is the development of new strategies for the prevention, detection and treatment of breast cancer that will come from learning what additional genes and pathways are important in breast tumorigenesis and those that are particularly relevant to early-onset breast cancer.