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，中位复发时间较短， 死亡人数高于其他乳腺癌患者。因为这些癌症的定义是缺乏靶点，识别 量身定做的疗法一直是具有挑战性的。然而，免疫疗法在TNBC中显示出重要的前景， 包括FDA对乳腺癌免疫疗法的第一次批准，以及对 在新辅助化疗的基础上增加免疫治疗。最近的证据表明，肿瘤分子 这些特征可能为TNBCs的不同病因和预后提供线索。基因表达 研究表明，TNBCs是异质性的，由更精细的亚型组成，部分由免疫定义 回复签名。据推测，患者的免疫反应在疾病中起着重要作用 决定肿瘤的进展。此外，测序研究已经确定了一组经常 在乳腺肿瘤和几个反映不同突变过程的突变特征中发生突变，并可能 有病因学的含义。在TNBCs中发现的突变特征与TNBCs中的 更常见的管腔乳腺癌，突出了针对这一亚型的研究的必要性。 我们建议对匹配的肿瘤和生殖系DNA样本进行完整的外显子组测序 来自四项前瞻性队列研究的400名TNBC患者，护士健康研究，护士健康研究 II、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 在生殖系GWA、乳腺癌风险因素和肿瘤免疫信号中，我们处于有利地位，可以更好地 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联。 突变图谱(目标1)和肿瘤免疫图谱(目标2)。我们还将研究两者之间的关联 免疫反应特征和肿瘤突变特征(目标3)。在探索性分析中，我们将评估 体细胞突变特征和免疫反应特征的可能联合作用 与乳腺癌特有的存活率有关(目标4)。从这项研究中获得的知识在 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团队。 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。首席调查员对队列资源有丰富的经验，并已 合作了超过13年。我们还与B-Cast和Amber财团合作 从TNBCs创建一个庞大且多样化的WES数据存储库，这将使我们能够复制我们的 结果和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.