Molecular pathoepidemiology of contralateral breast cancer

摘要 第一原发乳腺癌(BC)的幸存者发生第二次乳腺癌的风险增加2-5倍 原发于对侧乳房。BC的高发病率和存活率的提高导致了 数字(目前美国有近300万人)有患对侧乳腺癌(CBC)风险的女性。研究到 DATE已经确定了CBC的环境、遗传和治疗相关的风险因素。然而，尽管 CBC的病因学特征研究进展，很大一部分CBC的发病率仍未解释， 阻碍开发有效的风险分层或风险预测工具，这将是 为BC幸存者制定有效的CBC预防、监测和治疗策略。 在CBC风险的背景下，第一原发肿瘤反映了环境暴露和 主机功能，包括已知和可测量的功能以及未识别和/或 不可估量。首例原发肿瘤的分子特征可能是风险的有力补充指标 加拿大广播公司。在一项旨在提高风险分层能力的战略中，我们将使用尖端基因组 在CBC风险背景下询问第一原发肿瘤的技术。我们还将评估协调性 对配对的第一和第二原发肿瘤的分子特征进行研究以阐明对CBC生物学的见解 和潜在的共同的致病机制。 建议的研究建立在大型多中心WeCare研究的独特资源基础上 CBC的特点包括：以人群为基础确定CBC病例和对照(患有 单侧乳腺癌(UBC))；详细的临床资料，包括来自内科的首例原发BCS的治疗 记录审查；广泛的风险因素数据；正在进行的GWAS的生殖系基因数据；以及乳房X光检查 密度数据。我们将获得&gt；500个UBC对照和第一个原发乳腺肿瘤的肿瘤块 500例CBC中肿瘤加对侧肿瘤。实验室工作将包括：病理学审查； 转录组范围的肿瘤分子图谱；IHC分析；以及复制分析。 我们的主要目标是确定与风险相关的首例原发乳腺肿瘤的分子生物标志物 开发后续的CBC。我们将对第一个原发肿瘤进行RNA测序；确定大多数 信息性标记；开发与CBC相关的分子标记，并结合治疗进行联合评估 和生活方式/个人/医疗/生殖系遗传风险因素；并在 &gt；400个CBC病例和&gt；400个UBC对照的独立样本。我们的次要目标是：(1)研究 首次原发肿瘤的风险特征(建立在主要目标中)与CBC亚型特异性相关 风险；以及(2)评估配对中基因/转录本表达或改变和亚型的一致性 原发肿瘤和对侧肿瘤，并确定生活方式/个人/医疗/生殖系遗传 危险因素和治疗影响标记物一致性CBC的发生。

ABSTRACT Survivors of first primary breast cancer (BC) have a 2- to 5-fold increased risk of developing a second primary in the opposite breast. The high incidence and improved survival for BC has resulted in increasing numbers (currently nearly 3 million in U.S.) of women at risk of contralateral breast cancer (CBC). Studies to date have identified environmental, genetic, and treatment-related risk factors for CBC. However, despite advances in characterizing the etiology of CBC, a large fraction of CBC incidence remains unexplained, hindering the development of effective risk stratification or risk prediction tools which will be pivotal in developing effective CBC prevention, surveillance, and therapeutic strategies for BC survivors. In the context of CBC risk, first primary tumors reflect the joint effects of environmental exposures and host features, including those that are known and measurable as well as those that are unidentified and/or unmeasurable. Molecular features of first primary tumors could be powerful complementary indicators of risk of CBC. In a strategy designed to advance risk stratification capacity, we will use cutting edge genomic technologies to interrogate first primary tumors in the context of CBC risk. We will also assess the concordance of molecular features in paired first and second primary tumors to elucidate insights into the biology of CBC and potentially shared etiologic mechanisms. The proposed research builds on the unique resources of the large multi-center WECARE Study of CBC with features including: population-based ascertainment of CBC cases and controls (women with unilateral breast cancer (UBC)); detailed clinical data including treatment of first primary BCs from medical record reviews; extensive risk factor data; germline genetic data from an ongoing GWAS; and mammographic density data. We will obtain tumor blocks for first primary breast tumors of >500 UBC controls and first primary tumors plus contralateral tumors from > 500 CBC cases. Laboratory work will include: pathology reviews; transcriptome-wide molecular profiling of tumors; IHC analyses; and replication analyses. Our Primary Aim is to identify molecular biomarkers in first primary breast tumors associated with risk of developing a subsequent CBC. We will conduct: RNA-sequencing on first primary tumors; identify the most informative markers; develop a molecular signature associated with CBC and evaluate it jointly with treatment and lifestyle/personal/medical/germline genetic risk factors; and replicate with similar risk factors in an independent sample of > 400 CBC cases and > 400 UBC controls. Our Secondary Aims are to: (1) examine the risk signature in first primary tumors (established in the Primary Aim) in relation to CBC subtype-specific risk; and (2) assess the concordance of gene/transcript expression or alterations and subtypes in paired first primary and contralateral tumors and determine the extent to which lifestyle/personal/medical/germline genetic risk factors and treatment affect the development of marker-concordant CBC.