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。全氟烷基和多氟烷基物质 (PFAS) 是一类持久性、普遍存在的内分泌物质 破坏消费品和工业流程中常用的合成化学品。虽然他们是 低收入社区居民和少数族裔的居民发现，超过 97% 的美国人口中都检测到了这种病毒 许多 PFAS 物质的浓度更高。实验和动物数据支持 PFAS 的潜力 乳腺癌致癌物。流行病学数据好坏参半，但来自有限数量的前瞻性研究的结果 主要针对欧洲白人女性的研究表明，多种 PFAS 化合物与 乳腺癌风险增加，并且与 PFAS 相关的代谢改变可能是这种关联的基础。 然而，没有来自不同种族群体的前瞻性数据。本研究的主要目标 目的是调查较高的 PFAS 暴露是否会增加美国不同人群患乳腺癌的风险 以及是否整合 PFAS 水平、代谢改变、遗传易感性和流行病学风险 乳腺癌的因素确定了乳腺癌风险增加的女性亚群。我们提出第一个也是最大的 前瞻性多种族研究将 PFAS 视为乳腺癌的新危险因素。利用预 多民族的诊断血液样本以及有关乳腺癌危险因素和基因组学的综合数据 队列（MEC）是加利福尼亚和夏威夷的一个种族多元化的前瞻性队列，我们​​提出了一个嵌套案例 - 对 1,600 名女性浸润性乳腺癌患者和 1,600 名匹配对照女性（12% 为非洲人）进行的对照研究 美国人，16% 拉丁裔，11% 夏威夷原住民，40% 亚裔美国人，21% 白人）。我们将利用最先进的 基于非靶向液相色谱和高分辨率质谱的艺术实验室技术 测量血浆 PFAS 和代谢组谱，并将这些综合测量结果与 创新的统计方法来评估 PFAS、代谢组、遗传学、风险的综合关联 因素和乳腺癌风险。我们的具体目标是：（1）检查预诊断之间的关联 血浆 PFAS 水平与浸润性乳腺癌的风险； (1a) 评估各个 PFAS 和 具有乳腺癌风险的诊断前血浆样本中的 PFAS 混合物； (1b) 检查是否遗传 由多基因风险评分 (PRS) 确定的易感性改变了个体 PFAS 与 PFAS混合物具有患乳腺癌的风险； (2) 检查诊断前代谢组学之间的关联 (a) PFAS 暴露情况和 (b) 浸润性乳腺癌风险概况； (3) 整合 PFAS 浓度， 代谢组学测量、PRS 和其他乳腺癌危险因素，以确定乳腺癌风险增加的女性亚组 使用创新的潜变量分析来确定乳腺癌的风险。这项研究依赖于多学科团队 拥有环境和癌症流行病学专业知识的国际公认研究人员，以及国家 最先进的高分辨率代谢组学、基因组学和统计方法。研究结果有可能提供信息 为不同人群预防乳腺癌的精准医学方法，并影响政策变化。