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。年轻女性的乳腺肿瘤通常是ER阴性的，来自非裔美国人患者，并有其他高风险指标：然而，多变量分析表明，年轻本身是不良预后的独立预测因素。至少部分由于国防部服务的患者群体的独特性质，WRNMMC发现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。温德伯研究所主办的CBCP组织库在OCT上有40个肿瘤，这些样本可以从血液凝块中获得生殖系DNA。因此，有足够的数字来获取有意义的数据。来自年轻患者的肿瘤将被直接与使用相同平台的老年女性的生物库中的肿瘤进行比较。这些肿瘤将接受完整的外显子组测序、RNAseq和蛋白质组分析。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。所有这些样本都根据肿瘤的临床分类(腔A、腔B、HER2+和三阴性)进行了临床注释。对于从WRNMMC登记的患者，大多数病例都有结果数据，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。尽管患有乳腺癌的年轻女性预后不佳，但几乎没有研究，也没有专门的临床试验可用。该项目及其进一步发展可能是该领域的重大进展。目的2：乳腺癌化生和炎性肿瘤的探索性分析。化生和炎性乳腺癌是两种罕见的侵袭性乳腺癌(分别为1%和2%-3%)。对于这些亚型中的每一个，驱动这些亚型的突变都没有得到很好的描述。不幸的是，由于这类肿瘤的发生率很低，OCT中每种肿瘤只有4例(每种肿瘤中只有3例具有匹配的生殖系DNA)，因此这是一个探索性目标，我们将如上所述地处理这些肿瘤。对于每个DNA匹配的3个外显子，我们将进行完整的外显子测序和RNAseq。对于没有匹配生殖系DNA的样本，我们将只进行RNAseq。同样，在资金允许的情况下，我们将使用梅尔泽博士开发的OncoVar试验。现有的样本太少，无法给我们提供疾病的真实光谱，但可以想象的是，可以识别可能是这些子集所特有的新突变。我们将寻求通过与其他机构(如JHU、WHC)合作来扩大这些群体，以增加每个机构的样本量。目的3：在美国国防部数据库中对年轻女性、化生和炎症性乳腺癌进行生物信息学分析。国防部在链接的MDR和国防部CCR数据库中拥有1998-2007年间在国防部机构接受治疗的14,588名乳腺癌患者的临床数据(未来的更新将包括到2012年接受治疗的患者)。我们将与MCC军事人口科学和流行病学中心的朱康民博士合作，并在WMB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，我们也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提出，并发表在乳腺癌研究和治疗的一篇论文中。

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.