Molecular pathoepidemiology of contralateral breast cancer

摘要 第一次原发性乳腺癌（BC）的幸存者发生第二次乳腺癌的风险增加2至5倍。 原发于对侧乳房。BC的高发病率和生存率的提高导致了 数字（目前在美国近300万）对侧乳腺癌（CBC）的风险。研究来 迄今为止，已经确定了CBC的环境，遗传和治疗相关的风险因素。但尽管 CBC病因学特征的进展，CBC发病率的很大一部分仍然无法解释， 阻碍了有效的风险分层或风险预测工具的发展，这将是关键， 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，第一原发性肿瘤反映了环境暴露的联合影响， 主机特征，包括已知和可测量的特征，以及未识别和/或 无法衡量第一原发肿瘤的分子特征可能是恶性肿瘤风险的有力补充指标。 全血细胞计数在一项旨在提高风险分层能力的战略中，我们将使用尖端的基因组技术， 在CBC风险背景下询问第一原发肿瘤的技术。我们还将评估 配对的第一和第二原发性肿瘤的分子特征，以阐明CBC生物学的见解 和潜在的共同病因机制。 拟议的研究建立在大型多中心WECARE研究的独特资源基础上， CBC的特征包括：基于人群的CBC病例和对照的确定（患有 单侧乳腺癌（UBC））;详细的临床数据，包括来自医疗机构的首次原发性BC的治疗 记录审查;广泛的风险因素数据;来自正在进行的GWAS的生殖系遗传数据;以及乳房X光检查 密度数据我们将获得>500 UBC对照的第一原发性乳腺肿瘤的肿瘤块和第一原发性乳腺肿瘤的肿瘤块。 肿瘤加上对侧肿瘤，来自> 500个CBC病例。实验室工作将包括：病理学审查; 肿瘤的全转录组分子谱分析; IHC分析;和复制分析。 我们的主要目的是确定与风险相关的第一原发性乳腺肿瘤的分子生物标志物 建立一个后续的CBC。我们将进行：对第一个原发性肿瘤进行RNA测序;识别最重要的肿瘤。 信息标记物;开发与CBC相关的分子标记，并与治疗联合评估 和生活方式/个人/医疗/生殖系遗传风险因素;并在一个 > 400个CBC病例和> 400个UBC对照的独立样本。我们的目标是：（1）检查 与CBC亚型特异性相关的首个原发性肿瘤（在主要目的中确立）的风险特征 风险;和（2）评估配对第一组中基因/转录本表达或改变和亚型的一致性。 原发性和对侧肿瘤，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志物一致CBC的发展。

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.