Identification of Etiologically Distinct Sub-Types of Breast Cancer

描述(申请人提供)：这项建议的前提是，乳腺癌实际上是一个集合，这一事实阻碍了乳腺癌风险因素的检测 具有不同病因的疾病。如果我们能够定义我们确信在病因上不同的乳腺癌亚型，那么我们就可以进行研究，通过在亚型中寻找新的风险因素，以更有效、更具统计学效力的方式发现新的遗传风险因素。我们的论文认为，通过检查对侧乳腺癌患者肿瘤对的分子特征的相关性，可以获得建立病因上不同的亚型的独特见解。我们将使用一项已完成的乳腺癌病例对照研究(癌症和类固醇激素(CASH)研究)中的档案肿瘤和正常组织作为这些想法的原型研究，该研究涉及对侧癌症发生的病例的随访。这项研究将遵循一系列合理的步骤。在目标1中，我们将在表达模式I的基础上对对侧肿瘤进行分析，这是乳腺癌相关途径中的一组定制基因，以及全球微小RNA的表达，以检查这些特征的一致性。这些信息将被用来定义具有最大病因学异质性证据的亚型。在AIM中，从更大的乳腺癌发病病例中收集的2个肿瘤标本将进行类似的概况分析，并将其归类为第一个AIM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表明选定的风险因素的影响主要集中在个别肿瘤亚型上。最后，在AIM中，将使用病例中的3个正常组织来获得关于生殖系变异的定制小组的信息，并将探索这些信息以识别特定于或集中在一种或另一种肿瘤亚型中的变异。这项研究将利用现有的数据和来自档案病例对照研究的样本来进行研究策略的原型调查，该研究策略有可能 大大提高了乳腺癌和其他癌症部位未来流行病学研究的成果。

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.