Prediagnostic exposures, germline genetics, and triple negative breast cancer mutational and immune profiles

三阴性乳腺癌（TNBC）是典型的侵袭性癌症，复发的中位时间较短， 死亡率高于其他乳腺癌。由于这些癌症是由缺乏一个目标，识别 量身定制的治疗一直是个挑战。然而，免疫疗法在TNBC中显示出重要的前景， 包括FDA首次批准用于乳腺癌免疫治疗，以及 在新辅助化疗中增加免疫治疗。最近的证据表明肿瘤分子 这些特征可以为TNBC的不同病因学和疾病提供线索。基因表达 研究表明，TNBC是异质性的，由更精细的亚型组成，部分由免疫组织化学定义。 响应签名。据推测，患者的免疫反应在免疫系统中起着重要作用。 确定肿瘤进展。此外，测序研究已经确定了一组基因， 在乳腺肿瘤中发生突变，几种突变特征反映了不同的致突变过程， 都有病因学上的意义已在TNBC中鉴定的突变特征与在TNBC中鉴定的突变特征不同。 更常见的管腔型乳腺癌，突出了对这种亚型进行特定研究的必要性。 我们建议对匹配的肿瘤和生殖系DNA样本进行全外显子组测序（WES） 来自四项前瞻性队列研究的400名TNBC患者，护士健康研究， 癌症预防研究II和癌症预防研究3。结合我们现有的丰富数据库 生殖系GWAS，乳腺癌风险因素和肿瘤免疫特征，我们有能力更好地 了解遗传和非遗传风险因素如何影响乳腺肿瘤突变特征，免疫 反应和预后。我们将评估遗传和非遗传危险因素与肿瘤的关系 突变谱（Aim 1）和肿瘤免疫谱（Aim 2）。我们还将研究 免疫应答特征和肿瘤突变谱（Aim 3）。在探索性分析中，我们将评估 体细胞突变特征和免疫应答特征的可能联合效应是否 与乳腺癌特异性生存率相关（目标4）。这项研究的知识将是非常有价值的， 为这些侵袭性肿瘤制定预防策略和治疗目标。 为了实现这些目标，我们组建了一个多学科的乳腺癌专家小组， 流行病学、遗传流行病学、统计遗传学、生物信息学、免疫肿瘤学和肿瘤 基因组学主要研究者在队列资源方面拥有丰富的经验， 合作超过13年。我们还与B-CAST和AMBER财团合作， 创建一个来自跨国公司的大型和多样化的WES数据库，这将使我们能够复制我们的 结果，并比较突变谱及其与诊断前和临床因素的关系， 欧洲血统和非洲裔美国妇女。

Triple negative breast cancer (TNBC) are typically aggressive cancers with shorter median time to relapse and death than other breast cancers. Because these cancers are defined by the absence of a target, identification of tailored therapies has been challenging. However, immune therapy shows important promise in TNBC, including the first FDA approval for immunotherapy in breast cancer and favorable response data for the addition of immunotherapy to neoadjuvant chemotherapy. Recent evidence suggests that tumor molecular characteristics may provide clues to both the different etiology and prognoses for TNBCs. Gene expression studies revealed that TNBCs are heterogeneous and composed of finer subtypes, defined in part by immune response signatures. It has been hypothesized that the patients’ immune response plays an important role in determining tumor progression. Further, sequencing studies have identified a set of genes that are frequently mutated in breast tumors and several mutational signatures that reflect distinct mutagenic processes, and may have etiologic implications. The mutational signatures that have been identified in TNBCs are distinct from the more common luminal breast cancers, highlighting the need for research specific to this subtype. We propose to perform whole exome sequencing (WES) of matched tumor and germline DNA samples from 400 TNBC patients from four prospective cohort studies, the Nurses’ Health Study, Nurses’ Health Study II, Cancer Prevention Study II, and Cancer Prevention Study 3. In combination with our existing rich database of germline GWAS, breast cancer risk factors, and tumor immune signatures, we are well positioned to better understand how genetic and nongenetic risk factors influence breast tumor mutational signatures, immune response and prognosis. We will assess the association of genetic and nongenetic risk factors with tumor mutational profiles (Aim 1), and tumor immune profiles (Aim 2). We will also examine the association between immune response signatures and tumor mutation profiles (Aim 3). In exploratory analyses, we will evaluate whether a possible joint effect of somatic mutational signatures and immune response signatures are associated with breast cancer-specific survival (Aim 4). Knowledge from this study will be extremely valuable in developing prevention strategies and treatment targets for these aggressive tumors. To complete these aims, we have assembled a multidisciplinary team of experts in breast cancer epidemiology, genetic epidemiology, statistical genetics, bioinformatics, immuno-oncology, and tumor genomics. The Principal Investigators have extensive experience with the cohort resources and have worked collaboratively for over thirteen years. We have also partnered with the B-CAST and AMBER consortia to create a large and diverse repository of WES data from TNBCs, which will enable us to both replicate our results and compare mutational profiles and their associations with prediagnostic and clinical factors in European-ancestry and African American women.