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.

摘要。全氟烷基和多氟烷基物质（PFAS）是一类持久的、普遍存在的和内分泌的物质。 破坏消费品和工业过程中常用的合成化学品。虽然他们是 在超过97%的美国人口中检测到，低收入社区和少数民族的居民显示， 许多PFAS物质的浓度更高。实验和动物数据支持PFAS作为潜在的 乳腺致癌物流行病学数据喜忧参半，但结果来自有限数量的前瞻性研究。 在主要是欧洲白色妇女中进行的研究表明，几种PFAS化合物与 乳腺癌的风险增加，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-民族人群的前瞻性数据。本研究的主要目标 是调查在美国不同人群中，较高的PFAS暴露是否会增加乳腺癌的风险。 以及PFAS水平、代谢改变、遗传易感性和流行病学风险的整合是否 乳腺癌的因素确定了风险增加的妇女亚组。我们提出了第一个也是最大的 前瞻性多种族研究，以检查PFAS作为乳腺癌的新风险因素。利用前- 多种族妇女的诊断血液样本和乳腺癌风险因素和基因组学的综合数据 队列（MEC），在加州和夏威夷的种族多样性前瞻性队列，我们提出了一个嵌套的情况下- 对1，600名女性浸润性乳腺癌患者和1，600名匹配的对照女性（12%为非洲人）进行了对照研究。 美国人，16%拉丁美洲人，11%夏威夷土著人，40%亚裔美国人和21%白色）。我们将利用国家的- 基于非靶向液相色谱和高分辨率质谱的最新实验室技术 测量血浆PFAS和代谢组学特征，并将这些综合测量与联合收割机结合起来， 创新的统计方法来评估PFAS，代谢组学，遗传学，风险 因素和乳腺癌风险。我们的具体目标是：（1）检查诊断前 PFAS的血浆水平和浸润性乳腺癌的风险;（1a）评估个体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混合物与乳腺癌风险;（2）检查诊断前代谢组学之间的关系， （a）PFAS暴露和（B）浸润性乳腺癌风险的曲线;（3）整合PFAS浓度， 代谢组学测量、PRS和其他乳腺癌风险因素，以确定增加的女性亚组 乳腺癌的风险使用创新的潜在变量分析。这项研究依赖于一个多学科的团队 在环境和癌症流行病学方面具有专业知识的国际公认的调查人员，以及国家- 最先进的高分辨率代谢组学、基因组学和统计学方法。调查结果有可能为 为不同人群提供预防乳腺癌的精准医学方法，并影响政策变化。