Genomic characterization of breast cancer in high risk subsets of breast cancer

40岁以下的女性约占乳腺癌患者的5%，但大量研究表明，与年龄较大的女性相比，她们的预后更差，结果也更差。来自年轻女性的乳腺肿瘤通常为er阴性，来自非裔美国患者，并具有其他高风险指标：然而，多变量分析表明，年轻本身是预后不良的独立预测因子。至少部分原因是由于国防部所服务的患者群体的独特性质，在wnmmc中看到了不成比例的年轻女性乳腺癌病例。因此，CBCP纳入了大量40岁以下的浸润性乳腺癌患者，使我们有可能提出这项研究。位于Windber研究所的CBCP组织库在OCT中有40个肿瘤，这些肿瘤样本可以从血凝块中获得生殖系DNA。因此，有足够的数字来获得有意义的数据。使用相同的平台，年轻患者的肿瘤将直接与来自老年女性的生物库中的肿瘤进行比较。肿瘤将进行全外显子组测序、RNAseq和蛋白质组学分析。这些分析将使我们能够确定年轻女性肿瘤中所见的突变谱。所有样本均根据肿瘤临床分类（Luminal A、Luminal B、HER2+、三阴性）进行临床注释分组。对于从WRNMMC纳入的患者，大多数病例都有结果数据，并且正在收集更多的结果数据。这些分析将与公开可用的乳腺癌数据库（例如TCGA）进行比较，以验证我们数据中年轻和老年队列之间的差异。尽管年轻女性乳腺癌的预后较差，但很少有研究，也没有临床特异性临床试验。这个项目及其进一步发展可能是该领域的一个重大进展。目标2;乳腺癌肿瘤化生与炎性的探索性分析。化生性乳腺癌和炎症性乳腺癌是两种罕见的侵袭性乳腺癌（分别为1%和2-3%）。对于每一种，驱动这些亚型的突变都没有很好地表征。不幸的是，由于此类肿瘤的频率较低，OCT中每种只有4个（每种只有3个具有匹配的种系DNA），因此本目标是一个探索性目标，我们将如上所述处理肿瘤。对DNA匹配的3个进行全外显子组测序和RNAseq。对于没有匹配种系DNA的样本，我们将只执行RNAseq。如果资金允许，我们将使用Melzer博士开发的OncoVar检测。现有的样本太少，无法给我们提供疾病的真实谱，但可以想象识别出这些亚群可能独有的新突变。我们将透过与其他机构（例如JHU、WHC）的合作，扩大这些群组，以增加每个机构的样本量。目的3:DOD数据库中年轻女性、化生和炎症性乳腺癌的生物信息学分析。国防部在链接的MDR和国防部CCR数据库中拥有1998-2007年间在国防部设施接受治疗的14,588名乳腺癌患者的临床数据（未来将更新到2012年）。我们将与MCC军事人口科学与流行病学中心的朱康民博士合作，并在世界卫生组织的Alexandra Zimmer博士的协助下，使用该数据库调查年轻女性癌症的发病率，并跟踪治疗和结果。如果数量足够，我们还将在化生和炎症性癌症中探索这些问题。来自国防部数据库的数据已经在圣安东尼奥乳腺癌研讨会上作为海报讨论，并发表在《乳腺癌研究与治疗》杂志上。

Women under the age of 40 account for approximately 5% percent of breast cancer patients but numerous studies have shown that they have a worse prognosis and poorer outcome than women diagnosed at older ages. Breast tumors from young women are often ER-negative, from African-American patients and have other indicators of high risk: yet, multivariate analyses demonstrated that young age, in and of itself, is an independent predictor of poor outcome. At least partially due to the unique nature of the patient population served by DOD, a disproportionate number of breast cancer cases in young women are seen at WRNMMC. Thus CBCP has enrolled a good number of invasive breast cancer patients under 40 making it possible for us to propose this study. The CBCP Tissue Bank hosted at the Windber Research Institute has 40 tumors in OCT with germ line DNA available from blood clots for these sample. Thus there are sufficient numbers to get meaningful data. The tumors from young patients will be directly compared to those in the biobank from older women using the same platforms. The tumors will undergo whole exome sequencing, RNAseq, and proteomic analysis. These analyses will allow us to determine the spectrum of mutations seen in tumors from young women. All of these samples are clinically annotated into groups based on the clinical classification of the tumors (Luminal A, Luminal B, HER2+, and triple negative). For patients enrolled from the WRNMMC, most of the cases have outcome data and more outcome data is being collected. These analyses will be compared to the publicly available databases for breast cancer (e.g. TCGA) in order to validate differences between the younger and older cohort in our data. Despite the poor prognosis of young women with breast cancer, little research and no clinical specific clinical trials are available. This project and its further development could represent a major advance in the field. Aim 2; Exploratory analysis of metaplastic and inflammatory breast cancer tumors. Metaplastic and inflammatory breast cancer are two rare (1% and 2-3%, respectively) types of aggressive breast cancer. For each of these, the mutations that drive these subtypes are not well characterized. Unfortunately, due to the low frequency of such tumors, there are only 4 of each of these in OCT (and only 3 of each with matching germline DNA) so that this Aim is an exploratory aim in which we will approach the tumors as above. For the 3 of each with matching DNA we will perform whole exome sequencing and RNAseq. For the samples without matching germline DNA, we will perform only RNAseq. Again, as funding permits we will use the OncoVar assay developed by Dr. Melzer. The existing samples are too few to give us a true spectrum of the diseases but could conceivable identify novel mutations that might be unique to these subsets. We will seek to expand these cohorts through collaboration with other institutions (e.g. JHU, WHC) to increase the sample size of each. Aim 3: Bioinformatic analysis of young women, metaplastic, and inflammatory breast cancer in the DOD databases. The DOD has clinical data in the linked MDR and DoD CCR databases on 14,588 breast cancer patients treated at DOD facilities between 1998-2007 (with future updates to include those treated through 2012). In collaboration with Dr. Kangmin Zhu at the MCC for Military Population Sciences and Epidemiology and assisted by Dr. Alexandra Zimmer from the WMB, we will use the database to investigate the incidence of the cancers in young women and track treatment and outcomes. If the numbers are sufficient, we will also explore these questions in metaplastic, and inflammatory cancers. The data from the DOD data bases has been presented as a poster discussion at the San Antonio Breast Cancer Symposium and published in a paper in Breast Cancer Research and Treatment.