Molecular pathoepidemiology of contralateral breast cancer

对侧乳腺癌的分子病理流行病学

基本信息

批准号：
9905371
负责人：
JONINE L. BERNSTEIN
金额：
$ 201.62万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905371
关键词：
Acute Address Affect Biological Markers Biology Breast Breast Cancer Prevention Breast Cancer Risk Factor Breast Cancer survivor Cancer Control Characteristics Classification Clinical Clinical Data Clinical Trials Complement Contralateral Contralateral Breast Data Development Environmental Exposure Etiology Face Foundations Gene Expression General Population Genes Genetic Genomics Goals Immunohistochemistry Incidence Individual Joints Knowledge Laboratories Life Style Mammary Neoplasms Mammographic Density Measurable Measures Medical Medical Records Modeling Molecular Molecular Profiling Participant Pathology Population Prevention strategy Primary Neoplasm Radiation Research Resources Risk Risk Factors Risk stratification Sampling Second Primary Cancers Series Surveys Survivors Technology Therapeutic Transcript Tumor Tissue Validation Woman Work anticancer research base breast cancer survival cancer subtypes case control clinical decision-making design environment related cancer epidemiology study follow-up genetic risk factor genome wide association study high risk improved innovation insight malignant breast neoplasm molecular marker molecular subtypes next generation sequencing novel outcome forecast population based risk prediction model study population tool transcriptome transcriptome sequencing treatment response tumor

项目摘要

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.

抽象的第一原发性乳腺癌 (BC) 的幸存者患第二原发性乳腺癌的风险增加 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存在对侧乳腺癌 (CBC) 风险的女性人数（目前美国接近 300 万）。研究到迄今为止，已经确定了 CBC 的环境、遗传和治疗相关风险因素。然而，尽管 CBC 病因学特征的进展，很大一部分 CBC 发病率仍无法解释，阻碍了有效的风险分层或风险预测工具的开发，而这对于为 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，第一个原发性肿瘤反映了环境暴露和宿主特征，包括已知和可测量的特征以及未识别和/或无法测量的。第一个原发性肿瘤的分子特征可能是强有力的补充风险指标加拿大广播公司。在旨在提高风险分层能力的策略中，我们将使用尖端的基因组学在 CBC 风险背景下检查第一个原发性肿瘤的技术。我们还将评估一致性配对第一和第二原发肿瘤的分子特征，以阐明对 CBC 生物学的见解以及潜在的共同病因机制。拟议的研究建立在大型多中心 WECARE 研究的独特资源之上 CBC 的功能包括：基于人群确定 CBC 病例和对照（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例原发性 BC 的治疗记录评论；广泛的风险因素数据；来自正在进行的 GWAS 的种系遗传数据；和乳房X光检查密度数据。我们将获得> 500个UBC对照的第一个原发性乳腺肿瘤和第一个原发性乳腺肿瘤的肿瘤块。肿瘤加上来自 > 500 CBC 病例的对侧肿瘤。实验室工作将包括：病理学审查；肿瘤的全转录组分子分析； IHC 分析；和复制分析。我们的主要目标是确定与风险相关的第一个原发性乳腺肿瘤的分子生物标志物开发后续 CBC。我们将进行：对第一个原发性肿瘤进行 RNA 测序；识别最信息标记；开发与 CBC 相关的分子特征并与治疗联合评估以及生活方式/个人/医疗/种系遗传风险因素；并在类似的风险因素中进行复制 > 400 个 CBC 病例和 > 400 个 UBC 对照的独立样本。我们的次要目标是：（1）检查与 CBC 亚型特异性相关的第一个原发性肿瘤的风险特征（在主要目标中确定）风险; (2) 首先评估配对中基因/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/医学/种系遗传的程度危险因素和治疗会影响标志物一致的 CBC 的发展。