Molecular Discriminators in Benign Breast Tissue for Future Risk of ER positive a

描述(由申请人提供)：这项工作的长期目标是通过识别导致乳腺癌早期启动/易感的分子事件来推进乳腺癌预防和风险预测。目前的乳腺癌预防疗法被证明在减少雌激素受体阳性(ER+)癌症方面有效，但在预防ER阴性(ER-)癌症方面没有效果。这种预防乳腺癌的不同作用提供了强有力的证据，表明ER+和ER-癌症有不同的致癌途径，但肿瘤发生的最早步骤仍然知之甚少。此外，目前还没有准确预测单个女性患ER+或ER-乳腺癌风险的方法。通过对乳腺癌前病变组织的研究来研究乳腺癌的早期驱动因素，将为风险预测提供生物标志物的信息，并为新的预防策略提供相关途径。在这项研究计划中，将在一大批接受良性乳腺活检的妇女中进行良性乳腺活检组织的高通量分子研究，以获得关于后来的乳腺癌和肿瘤的ER状态的信息。病例对照子集将从队列中发展出来，具有相同数量的ER+、ER-和对照受试者。在目标1中，我们将执行基因表达谱分析，并创建与ER+和ER-乳腺癌风险相关的基因签名。在目标2中，将评估良性乳腺活检组织中选定的候选驱动突变(根据已发表的研究结果最常见)及其与ER+和ER-乳腺癌风险的关系。一组配对的乳腺组织和生殖系DNA样本将进行完整的外显子组测序，以研究与癌症相关的体细胞突变。在图谱研究中确定的基因路径将与驱动程序突变相关。在目标3中，关于良性乳腺疾病组织中基因表达谱和体细胞突变的信息将用于改善ER+和ER-乳腺癌的风险分层。这项工作将产生预测ER+和ER-BC的基因签名，这可能会改善ER+BC的风险预测，并增加ER+预防治疗的接受度。ER-BC风险的基因组签名将有助于确定ER-BC的关键致癌途径和新的预防治疗方法。

DESCRIPTION (provided by applicant): The longterm objective of this work is to advance breast cancer prevention and risk prediction by identifying molecular events underlying early initiation/predisposition to breast cancer. Current prevention therapies for breast cancer are proven to be effective at reducing estrogen receptor positive (ER+) cancers but have no impact on preventing ER negative (ER-) cancers. This differential effect on breast cancer prevention provides strong evidence that ER+ and ER- cancers have different pathways to carcinogenesis, but the earliest steps in tumorigenesis remain poorly understood. Furthermore, there are no existing methods to accurately predict an individual woman's risk for either ER+ or ER- breast cancer. Investigation into early drivers of breast cancer through study of premalignant breast tissues will yield information on biomarkers for risk prediction and relevant pathways that may inform new prevention strategies. In this research proposal, high throughput molecular studies of benign breast biopsy tissues will be performed in a large cohort of women who underwent benign breast biopsy, with information available on later breast cancers and ER status of the tumors. A case control subset will be developed from the cohort, with equal numbers of ER+, ER-, and control subjects. In Aim 1 we will perform gene expression profiling and create gene signatures associated with risk of ER+ and ER- breast cancer. In Aim 2, benign breast biopsy tissues will be evaluated for select candidate driver mutations (the most common based on published findings) and their associations with risk of ER+ and ER- breast cancer. A subset of samples with paired breast tissue and germline DNA will undergo whole exome sequencing to investigate somatic mutations associated with cancer. Gene pathways identified in profiling studies will be correlated with driver mutations. In Aim 3, information on gene expression profiles and somatic mutations in benign breast disease tissues will be used to improve risk stratification for ER+ and ER- breast cancers. This work will result in the creation of gene signatures predictive of ER+ and ER- BC, which will likely improve risk prediction for ER+ BC and increase uptake of ER+ prevention therapies. Genomic signatures of ER- BC risk will help to identify key oncogenic pathways and new prevention treatments for ER- BC.