Identification of Etiologically Distinct Sub-Types of Breast Cancer

描述（由申请人提供）：该提案基于以下前提：乳腺癌风险因素的检测受到乳腺癌实际上是一个集合的事实的阻碍 不同病因的疾病。如果我们能够定义我们确信在病因学上具有异质性的乳腺癌亚型，那么我们就可以通过在亚型中寻找新的风险因素，以更有效，更强大的统计学方式进行研究，以发现新的遗传风险因素。我们的论文是，建立病因学上不同的亚型的独特见解，可以通过检查对侧乳腺癌妇女的肿瘤对的分子特征的相关性。我们将使用已完成的乳腺癌病例对照研究（癌症和类固醇激素（CASH）研究）中的存档肿瘤和正常组织作为这些想法的原型调查，该研究涉及对侧癌症发生的病例随访。这项研究将遵循一系列合乎逻辑的步骤。在目标1中，我们将根据乳腺癌相关通路中的一组自定义基因的表达模式和全球microRNA表达来分析对侧肿瘤对，以检查这些谱的一致性。该信息将用于定义具有最大病因异质性证据的亚型。在目标2中，将对来自大量乳腺癌偶发病例的肿瘤标本进行类似的分析，并将其分类为第一个目标中定义的亚型。这些亚型将与CASH研究中现有的已知乳腺癌风险因素进行比较，以确定新的分类系统是否证明选定风险因素的影响主要集中在单个肿瘤亚型上。最后，在目标3中，来自病例的正常组织将用于获得关于生殖系变异的定制面板的信息，并且这些将被探索以识别对于一种或另一种肿瘤亚型是独特的或集中在一种或另一种肿瘤亚型中的变异。这项研究将利用档案病例对照研究的现有数据和标本，对一项有可能 大大提高了乳腺癌和其他癌症部位未来流行病学研究的产量。

DESCRIPTION (provided by applicant): This proposal is based on the premise that detection of risk factors for breast cancer is hampered by the fact that breast cancer is really a collection of diseases with distinct etiologies. If we are able to define sub-types of breast cancer that we are convinced are etiologically heterogeneous then we can conduct studies to discover novel genetic risk factors in a more effective, statistically powerful way by searching for new risk factors within the sub-types. Our thesis is that unique insights for establishing etiologically distinct sub-types can be obtained by examining the correlations of molecular characteristics of tumor pairs in women with contralateral breast cancer. We will use archival tumor and normal tissue from a completed case-control study of breast cancer (the Cancer and Steroid Hormone (CASH) Study) that involved follow-up of the cases for the occurrence of a contralateral cancer to serve as a prototype investigation of these ideas. The study will follow a logical sequence of steps. In Aim 1 we will profile pairs of contralateral tumors on the basis of expression patterns i a custom panel of genes in pathways implicated in breast cancer and global micro RNA expression in order to examine the concordance of these profiles. This information will be used to define the sub-types with the greatest evidence for etiologic heterogeneity. In Aim 2 tumor specimens from a larger collection of incident cases of breast cancer will be similarly profiled and classified into the sub-types defined in the first aim. These sub-types will be compared with respect to existing, known risk factors for breast cancer that are available in the CASH Study to determine if the new classification system demonstrates that the impact of selected risk factors are focused primarily on individual tumor sub-types. Finally, in Aim 3 normal tissue from the cases will be used to obtain information on a custom panel of germ-line variants, and these will be explored to identify variants that are unique to or concentrated in one or other of the tumor sub-types. The study will make use of existing data and specimens from an archival case-control study to conduct a prototype investigation of a research strategy that has the potential to improve greatly the yield from future epidemiologic studies in both breast cancer and other cancer sites.