Molecular pathoepidemiology of contralateral breast cancer

对侧乳腺癌的分子病理流行病学

• 批准号: 10427192
• 负责人: JONINE L. BERNSTEIN
• 金额: $ 129.71万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427192
• 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; Prognosis; Radiation; Research; Resources; Risk; Risk Factors; 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; population based; risk prediction; risk prediction model; risk stratification; study population; tool; transcriptome; transcriptome sequencing; treatment response; tumor

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 第一乳腺癌（BC）的幸存者有2至5倍的发展风险 主要在相反的乳房中。卑诗省的高发病率和提高的生存率已导致增加 有对侧乳腺癌（CBC）风险的女性（目前在美国目前近300万）。研究 日期已经确定了CBC的环境，遗传和治疗相关的危险因素。但是，尽管如此 表征CBC病因的进展，很大一部分CBC发病率仍无法解释， 阻碍开发有效的风险分层或风险预测工具，这将是关键的 为卑诗省幸存者开发有效的CBC预防，监视和治疗策略。 在CBC风险的背景下，第一个原发性肿瘤反映了环境暴露和 主机功能，包括已知和可测量的功能以及未知和/或未识别的功能 无法衡量。第一个原发性肿瘤的分子特征可能是强大的互补指标 CBC。在旨在提高风险分层能力的策略中，我们将使用尖端基因组 在CBC风险的背景下，询问第一肿瘤的技术。我们还将评估一致性 配对的第一和第二个原发性肿瘤中的分子特征，以阐明对CBC生物学的见解 并有可能共享病因机制。 拟议的研究以大型多中心Wecare研究的独特资源为基础 CBC具有以下特征：基于人群的CBC病例和对照的确定（患有患有的女性 单侧乳腺癌（UBC））;详细的临床数据，包括对医学的第一个初级BC的处理 记录评论；广泛的风险因素数据；正在进行的GWAS的种系遗传数据；和乳房X线学 密度数据。我们将获得> 500个UBC对照和第一次初级肿瘤的肿瘤块 肿瘤加上> 500例CBC病例的对侧肿瘤。实验室工作将包括：病理评论； 肿瘤的整个转录组分子分析； IHC分析；和复制分析。 我们的主要目的是鉴定与风险相关的第一乳肿瘤中的分子生物标志物 开发随后的CBC。我们将进行：对第一个原发性肿瘤进行RNA测序；确定最多 内容丰富的标记；开发与CBC相关的分子签名，并通过治疗共同评估 以及生活方式/个人/医疗/种系遗传危险因素；并以类似的风险因素复制 > 400个CBC案例和> 400个UBC对照的独立样本。我们的次要目标是：（1）检查 与CBC亚型特异性有关的第一原发性肿瘤（主要目的建立）中的风险签名 风险; （2）评估基因/转录本表达或成对中的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/种系的程度 危险因素和治疗会影响标记符合CBC的发展。

项目成果

Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population.

• DOI: 10.1186/s13058-017-0874-x
• 发表时间: 2017-07-19
• 期刊: Breast cancer research : BCR
• 作者: Reiner AS;Lynch CF;Sisti JS;John EM;Brooks JD;Bernstein L;Knight JA;Hsu L;Concannon P;Mellemkjær L;Tischkowitz M;Haile RW;Shen R;Malone KE;Woods M;Liang X;Morrow M;Bernstein JL;WECARE Study Collaborative Group
• 通讯作者: WECARE Study Collaborative Group