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

抽象的。全氟烷基物质和多氟烷基物质是一类持久的、普遍存在的内分泌物质 扰乱消费品和工业过程中常用的合成化学品。当他们在 在97%的美国人口中检测到，低收入社区的居民和少数族裔显示 更高浓度的许多全氟辛烷磺酸物质。实验和动物数据支持全氟辛烷磺酸作为潜在的 乳房致癌物质。流行病学数据喜忧参半，但结果来自有限数量的前瞻性 在主要是欧洲白人妇女中进行的研究表明，几种全氟辛烷磺酸化合物与 乳腺癌风险的增加和与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-民族人口的预期数据。这项研究的主要目标是 是要调查较高的PFAS暴露是否会增加美国不同人群患乳腺癌的风险 以及PFAS水平、代谢变化、遗传易感性和流行病学风险的整合 乳腺癌的因素确定了风险增加的妇女亚群。我们提出了第一个也是最大的 前瞻性多种族研究，以检验全氟辛烷磺酸是乳腺癌的新危险因素。利用Pre- 多民族乳腺癌危险因素和基因组学诊断血样和综合数据 Cohort(MEC)是加利福尼亚州和夏威夷的一个种族多样化的潜在队列，我们提出了一个嵌套病例- 1600名女性浸润性乳腺癌患者和1600名匹配对照妇女(12%非洲人)的对照研究 美国人，16%拉美人，11%夏威夷原住民，40%亚裔美国人，21%白人)。我们将利用最新的- 基于非靶向高效液相色谱-高分辨质谱学的ART实验室技术 测量血浆全氟辛酸和代谢组谱，并将这些综合测量与 创新的统计方法来评估全氟辛烷磺酸、代谢组、遗传学、风险的综合关联 因素，和乳腺癌的风险。我们的具体目标是：(1)检查诊断前 血浆全氟辛烷磺酸水平与浸润性乳腺癌风险；(1a)评估个体全氟辛烷磺酸与 诊断前血浆样本中的PFAS混合物与乳腺癌风险；(1b)检查基因 由多基因风险分数(PRS)确定的倾向修改了单个PFAS和 PFAS混合物与乳腺癌风险；(2)检查诊断前代谢物之间的关联 概况(A)与全氟辛烷磺酸暴露和(B)浸润性乳腺癌风险；(3)整合全氟辛烷磺酸浓度， 代谢指标、PR和其他乳腺癌危险因素以确定增加的妇女亚组 使用创新的潜变量分析乳腺癌的风险。这项研究依赖于一个多学科的团队 拥有环境和癌症流行病学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、基因组学和统计方法。这些发现有可能为 针对不同人群的乳腺癌预防的精准医学方法，并影响政策变化。

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.