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。具有种系DNA的肿瘤将进行全外显子组测序和RNAseq。对于没有匹配种系DNA的肿瘤，我们将只执行RNAseq。在资金允许的情况下，我们还将使用Meltzer博士开发的OncoVar测试来评估样本，该测试可以测试超过250个已知在实体瘤中经常突变的基因的突变，缺失和易位。基因组分析将与NCI的Paul Meltzer合作完成。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。这些分析将与公开的乳腺癌数据库（如TCGA）进行比较，以确定肿瘤是否与老年妇女或整体乳腺癌中所见的突变具有不同的频谱或频率。这些数据应该有助于确定年轻女性风险增加的性质，因为这可能是由于肿瘤基因组学的差异，或者如果没有差异，则可能是由于肿瘤产生的环境。因此，在任何一种情况下，数据都将提供信息。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DoDCCR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。

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 with germline DNA available will undergo whole exome sequencing and RNAseq. For tumors without matching germline DNA we will perform RNAseq only. We would also, as funding allows, to assess the samples using the OncoVar test developed by Dr. Meltzer which can test for mutation, deletions, and translocations in more than 250 genes known to be frequently mutated in solid tumors. The genomic analysis will be done in collaboration with Paul Meltzer at the NCI. 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 publically available databases for breast cancer (e.g. TCGA) in order to determine if the tumors have a different spectrum or frequency of mutations from those seen in older women or breast cancer as a whole. These data should help define the nature of the increased risk in young women as it could be due to differences in tumor genomics, or if there is no difference, it could be due to the environment in which the tumors arise. Thus the data will be informative in either case. 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 DoDCCR 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.