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确定乳腺癌早期发病/易感性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已被证明在减少雌激素受体阳性（ER+）癌症方面有效，但对预防雌激素受体阴性（ER-）癌症没有影响。这种对乳腺癌预防的不同作用提供了强有力的证据，证明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，目前还没有方法可以准确预测个体女性患ER+或ER-乳腺癌的风险。通过对癌前乳腺组织的研究来研究乳腺癌的早期驱动因素，将获得用于风险预测的生物标志物和相关途径的信息，这可能为新的预防策略提供信息。在本研究计划中，良性乳腺活检组织的高通量分子研究将在一大批接受良性乳腺活检的女性中进行，以获得晚期乳腺癌和肿瘤ER状态的信息。将从该队列中建立一个病例对照子集，其中ER+、ER-和对照受试者人数相等。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特征。在Aim 2中，将评估良性乳腺活检组织中选择的候选驱动突变（基于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。一组具有配对乳腺组织和生殖系DNA的样本将进行全外显子组测序，以研究与癌症相关的体细胞突变。在谱分析研究中确定的基因通路将与驱动突变相关。在Aim 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的基因标记，这可能会改善ER+ BC的风险预测，并增加ER+预防治疗的采用。ER- BC风险的基因组特征将有助于确定关键的致癌途径和新的ER- BC预防治疗。

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.