A nested case-control study of perfluoroalkyl and polyfluoroalkyl substances (PFAS) and breast cancer risk in the Multiethnic Cohort

多种族队列中全氟烷基和多氟烷基物质 (PFAS) 与乳腺癌风险的巢式病例对照研究

• 批准号: 10639686
• 负责人: Eunjung Lee
• 金额: $ 68.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-26 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639686
• 关键词: Accounting; Address; Adult; African American; Age; Animals; Area; Asian; Asian Americans; Blood; Blood specimen; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Risk Factor; California; Cancer Etiology; Cancer Patient; Carcinogens; Cessation of life; Chemicals; Communities; Data; Development; Diagnosis; Diagnostic; Disparity; Endocrine Disruptors; Endocrine disruption; Environmental Epidemiology; Epidemiology; Ethnic Origin; Ethnic Population; European; Fasting; Female; Genetic; Genetic Predisposition to Disease; Genomics; Geographic Distribution; Glucose; Goals; Guidelines; Hawaii; Hispanic; Hormones; Hour; Incidence; Individual; Industrialization; International; Investigation; Japanese American; Latina; Latino; Life Style; Link; Lipids; Liquid Chromatography; Low income; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Metabolic Pathway; Minority Women; Native Hawaiian; Nested Case-Control Study; Not Hispanic or Latino; Participant; Pathway interactions; Plasma; Policies; Poly-fluoroalkyl substances; Population; Population Heterogeneity; Predisposition; Pregnancy; Process; Property; Prospective Studies; Prospective cohort; Race; Research; Research Personnel; Resolution; Risk; Risk Factors; Role; Sample Size; Sampling; Source; Statistical Methods; Subgroup; Testing; Woman; amino acid metabolism; animal data; cancer epidemiology; cancer risk; cohort; consumer product; data integration; diverse data; epidemiologic data; epidemiology study; ethnic diversity; ethnic minority; follow-up; innovation; insight; laboratory equipment; malignant breast neoplasm; mammary; metabolome; metabolomics; multi-ethnic; multidisciplinary; neoplasm registry; novel; polygenic risk score; precision medicine; prenatal exposure; prospective; racial diversity; racial minority; racial population

ABSTRACT. Per- and poly-fluoroalkyl substances (PFAS) are a class of persistent, ubiquitous, and endocrine disrupting synthetic chemicals commonly used in consumer products and industrial processes. While they are detected in >97% of the US population, residents of low-income communities and racial-ethnic minorities show greater concentrations of many PFAS substances. Experimental and animal data support PFAS as potential mammary carcinogens. Epidemiologic data have been mixed, but results from a limited number of prospective studies among primarily European white women suggest that several PFAS compounds are associated with increased risk of breast cancer and that metabolic alterations linked to PFAS might underlie the associations. However, no prospective data from diverse racial-ethnic populations are available. The primary goal of this study is to investigate whether higher PFAS exposure increases the risk of breast cancer in a diverse US population and whether integration of PFAS levels, metabolic alterations, genetic predisposition, and epidemiologic risk factors of breast cancer identifies subgroups of women at increased risk. We propose the first and largest prospective multi-ethnic study to examine PFAS as novel risk factors of breast cancer. Leveraging the pre- diagnostic blood samples and comprehensive data on breast cancer risk factors and genomics in the Multiethnic Cohort (MEC), an ethnically diverse prospective cohort in California and Hawaii, we propose a nested case- control study of 1,600 female invasive breast cancer patients and 1,600 matched control women (12% African American, 16% Latina, 11% Native Hawaiian, 40% Asian American, and 21% White). We will utilize state-of-the- art laboratory technologies based on untargeted liquid chromatography with high resolution mass spectrometry to measure plasma PFAS and metabolome profiles, and combine these comprehensive measurements with innovative statistical methods to evaluate the integrated associations of PFAS, metabolome, genetics, risk factors, and breast cancer risk. Our specific aims are: (1) To examine the association between pre-diagnostic plasma levels of PFAS and risk of invasive breast cancer; (1a) Evaluate the associations of individual PFAS and PFAS mixture in pre-diagnostic plasma samples with breast cancer risk; (1b) Examine whether genetic predisposition determined by a polygenic risk score (PRS) modifies the association of individual PFAS and the PFAS mixture with breast cancer risk; (2) To examine the association between pre-diagnostic metabolomic profiles (a) with PFAS exposures and (b) with invasive breast cancer risk; (3) To integrate PFAS concentrations, metabolomic measures, PRS, and other breast cancer risk factors to identify subgroups of women at increased risk for breast cancer using an innovative latent variable analysis. This research relies on a multidisciplinary team of internationally-recognized investigators with expertise in environmental and cancer epidemiology, and state- of-the-art high-resolution metabolomics, genomics and statistical methods. Findings have the potential to inform precision medicine approaches for breast cancer prevention for diverse populations, and to impact policy change.

抽象的。每类和多氟烷基物质（PFA）是一类持续，无处不在和内分泌 破坏在消费产品和工业过程中常用的合成化学物质。当他们是 在> 97％的美国人口中发现，低收入社区和种族少数民族的居民显示 许多PFA物质的浓度更高。实验和动物数据支持PFA作为潜力 乳腺癌。流行病学数据是混杂的，但是来自有限数量的前瞻性数据 主要是欧洲白人妇女的研究表明，几种PFA化合物与 乳腺癌的风险增加以及与PFA有关的代谢改变可能是协会的基础。 但是，没有来自不同种族种族人口的前瞻性数据。这项研究的主要目标 是调查较高的PFA暴露是否会增加美国人群中乳腺癌的风险 以及PFA水平的整合，代谢改变，遗传倾向和流行病学风险是否 乳腺癌的因素确定了风险增加的女性亚组。我们提出了第一个也是最大的 前瞻性多种族研究将PFA视为乳腺癌的新危险因素。利用前 诊断血液样本以及有关乳腺癌危险因素和基因组学的全面数据 队列（MEC）是加利福尼亚和夏威夷的种族多样性的前瞻性队列，我们​​提出了一个嵌套的病例 - 1,600名女性侵入性乳腺癌患者和1,600名匹配的对照妇女的对照研究（12％的非洲人 美国人，拉丁裔16％，夏威夷人11％，亚裔美国人40％，白人21％）。我们将利用最新 艺术实验室技术基于未靶向的液相色谱法，高分辨率质谱法 测量血浆PFA和代谢组曲线，并将这些综合测量与 评估PFA，代谢组，遗传学，风险的综合关联的创新统计方法 因素和乳腺癌风险。我们的具体目的是：（1）检查诊断前的关联 PFA的血浆水平和侵入性乳腺癌的风险； （1a）评估单个PFA和 患有乳腺癌风险的诊断前血浆样品中的PFA混合物； （1b）检查遗传是否 由多基因风险评分（PRS）确定的易感性修饰了单个PFA和 乳腺癌风险的PFA混合物； （2）检查诊断前代谢组之间的关联 带有PFAS暴露和（B）具有侵入性乳腺癌风险的特征（a）； （3）整合PFA浓度， 代谢组措施，PR和其他乳腺癌危险因素，以识别女性的亚组 使用创新的潜在可变分析患乳腺癌的风险。这项研究依赖于一个多学科团队 国际认可的研究人员在环境和癌症流行病学方面具有专业知识，以及国家 高分辨率代谢组学，基因组学和统计方法。调查结果有可能告知 精密医学方法用于预防乳腺癌的不同人群，并影响政策变化。