Environmental and Genetic Risk Factors For Breast Cancer: The Sister Study

乳腺癌的环境和遗传风险因素：姐妹研究

• 批准号: 10008717
• 负责人: Dale P Sandler
• 金额: $ 110.31万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10008717
• 关键词: 25-hydroxyvitamin D; Acids; Adherence; Affect; African American; Age; Air; Air Pollutants; Air Pollution; Alcohol consumption; Alternative Health; Analgesics; Area; Award; Biliary Tract Cancer; Biological; Birth; Blood; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Cancer gene; Breast Cancer survivor; Cadmium; Cancer Etiology; Cardiovascular Diseases; Cessation of life; Child; Childbirth; Cholesterol; Chromium; Chronic; Collaborations; Collection; Complex; DASH diet; DNA Methylation; Data; Data Set; Diagnosis; Diet; Dietary Factors; Disease; Domestic Fowls; Elements; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Estrogen receptor negative; Estrogens; Ethnic group; Etiology; Exposure to; Female; Follow-Up Studies; Frequencies; Genes; Genetic; Genotype; Glucose; Goals; Grant; Health; Health Status; Home visitation; Hour; Hypertension; In Situ; Incidence; Institutes; Insulin; Joints; Lead; Life Style; Light; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Meat; Medical; Medical Records; Mercury; Metabolic Diseases; Methylene Chloride; Mothers; North Carolina; Not Hispanic or Latino; Obesity; Onset of illness; Outcome; Overweight; Paper; Participant; Penicillins; Postmenopause; Potassium; Premenopause; Prospective Studies; Publishing; Questionnaires; Race; Randomized; Reporting; Research; Retrospective Studies; Risk; Risk Factors; Salts; Sampling; Serum; Sister; Site; Sleep; Solid Neoplasm; Structure of nail of toe; Styrenes; Surveys; Telephone Interviews; Television; Testing; Time; Trace Elements; Tumor Tissue; Universities; Urine; Vital Status; Vitamin D; Washington; Woman; Women' s Health; aged; anticancer research; breast cancer diagnosis; cancer subtypes; cardiovascular disorder risk; cohort; design; diet and cancer; experience; falls; follow-up; fruits and vegetables; gene environment interaction; genetic risk factor; genome wide association study; high risk; indexing; malignant breast neoplasm; methylation biomarker; mortality; mullerian-inhibiting hormone; obesity risk; pediatric trauma; propylene; prospective; red meat consumption; response; shift work

We are following 50,884 US women who were aged 35-74 and had a sister with breast cancer but did not have breast cancer themselves when they enrolled in 2003-2009. Enrollment data on potential risk factors and health status were collected using telephone interviews. Blood, urine, and environmental samples were collected in a home visit. To date, more than 3,500 participants reported a diagnosis of invasive or in situ breast cancer. The cohort is tracked annually for changes in vital status and major health outcomes. Detailed follow-up questionnaires on health outcomes, environmental and lifestyle exposures, and other topics are completed every 2-3 years. Medical records are retrieved for cancers and other priority conditions. Tumor tissue is obtained for breast cancers. The first Sister Study follow-up survey was completed in June 2012 with a response rate of 95%. The second and third detailed follow-up surveys were completed with better than 92% response. The fourth was launched in October 2017, with 85% responding as of July 2019. We have conducted several studies of dietary factors and breast cancer risk. One study failed to confirm a previously reported link between an estrogen-related diet and breast cancer. In another, we observed that high adherence to the Dietary Approaches to Stop Hypertension (DASH) diet was associated with reduced risk of breast cancer. Adherence to the Alternative Health Index was also associated with reduced breast cancer risk. We also found that women with high diet-dependent acid loads had a greater risk of developing breast cancer than those with low acid loads. This suggests that diets with decreased acid load, such as those abundant in fruits and vegetables and therefore rich in potassium salts, may protect against breast cancer. Additionally, we found that increasing consumption of red meat was associated with increased risk of invasive breast cancer whereas results suggested that replacing red meat with poultry could reduce breast cancer incidence. In the first of three studies of risk factors for obesity, we found that women who ate breakfast every morning were less likely to be or become obese, compared to women who irregularly ate breakfast (3-4 days a week). In the next, we found that chronic penicillin use may be associated with increased risk of obesity. Finally, we observed that exposure to artificial light at night while sleeping was associated with being or becoming overweight or obese, with stronger associations seen for those reporting lights or television on in the room. In 2014-15 we repeated the collection of biological and environmental samples and anthropometric measures from women diagnosed with breast cancer since enrollment and a random sample of women without breast cancer. Of approximately 3,800 participants invited, samples were collected from 2,436 (63%) including 1,229 women who had been diagnosed with breast cancer. So far, we have published three studies that made use of twice-collected biospecimens. In the first, we assessed concentrations of 16 trace elements from toenails collected at baseline and in 2014-15, finding that levels generally decreased over time, particularly for cadmium, chromium and lead. We used these results to better inform a study of trace elements and young-onset breast cancer, finding no evidence of associations for any of the measured elements, after correcting for differences in year of collection for cases versus controls. In another study, we observed that while both breast cancer cases and non-cases had higher serum 25-hydroxyvitamin D concentrations, on average, at the second time-point compared to the first, increases were greater in cases. Finally, we studied whether breast cancer survivors were more likely to develop cardiovascular disease risk factors (e.g. hypertension, high cholesterol, overweight) over time than women who did not have breast cancer, finding no difference. Breast cancer and ovarian cancer cases through 2014 and a random sample of the cohort have been genotyped as part of the multi-site Breast Cancer Association Consortium and Ovarian Cancer Association Consortium. Through these projects, Sister Study data have been included in several collaborative analyses, including: a study of predicted DNA methylation and breast cancer; a study of predicted DNA methylation and ovarian cancer; a study of vitamin D-related genes and ovarian cancer; a genome-wide association study (GWAS) of Anti-Mullerian hormone (AMH) levels; a GWAS of six solid tumor cancers; a Mendelian randomization study of obesity, insulin, glucose and breast cancer; and a study of a polygenic risk scores, breast cancer, and breast cancer subtypes. We additionally lead or are contributing to several other consortium projects, including the Premenopausal Breast Cancer Collaboration with primary collaborators Hazel Nichols (University of North Carolina) and Anthony Swerdlow and Minouk Schoemaker (Institute for Cancer Research, UK). To date more than 20 cohorts have joined this effort. In a paper published last year, we showed that higher BMI was associated with reduced risk of premenopausal breast cancer. We also showed that breast cancer risk is increased shortly after breast cancer for women who have given birth compared to women who do not have children; childbirth doesnt become protective for breast cancer until 20 more years after childbirth. Projects from other consortia include a study of analgesic use and ovarian cancer, a study of AMH and breast cancer risk prediction, and two studies of risk factors for biliary tract cancers. Dr. Alexandra White led efforts to identify environmental risk factors for breast cancer using publicly available data sets to look at participants estimated exposure to air toxics. We found that women who lived in areas of higher airborne cadmium, lead and mercury were at a higher risk of developing postmenopausal breast cancer. Other air pollutants, including methylene chloride, propylene dichloride, polycyclic organic matter, and styrene, were associated with a higher risk of breast cancer. Dr. White was recently awarded a grant through the Office of Research on Womens Health to study how trace elements (as measured in toenail samples) may be related to breast cancer risk. In addition, we have collaborated with Dr. Joel Kaufman (University of Washington) to study criteria air pollutants and breast cancer and a new collaboration considers the association between air pollution and cardiovascular disease in the Sister Study, an effort that will be expanded to include breast cancer. In an initiative led by Dr. Jack Taylor, we previously generated data on 450,000 CpGs for the non-Hispanic white women in the genotyping sample. We have now reported on several thousand sites associated with breast cancer risk, many of which may be useful in detecting early stage invasive breast cancer. We also identified CpGs associated with alcohol use and mothers age at birth. One of our most significant contributions has been in the field of epigenetic age, a biological measure of age quantified using specific DNA methylation markers. We observed a positive association between three epigenetic age clocks and breast cancer. In subsequent analyses, we found associations between epigenetic age and both shift work and air pollution. Dr. Taylors group plans a new DNA methylation study that will focus on African-American women and estrogen receptor negative breast cancer. Dr. Chandra Jacksons group has been using Sister Study data to study predictors and health effects of sleep. We found that women who experienced childhood trauma reported worse sleep. In another study, we showed that women who averaged less than 7 hours of sleep per night and who had difficulty falling or staying asleep were more likely to have metabolic disorders.

我们追踪了 50,884 名美国女性，她们年龄在 35 岁至 74 岁之间，她们的姐妹患有乳腺癌，但她们在 2003 年至 2009 年入组时并未患有乳腺癌。通过电话访谈收集有关潜在危险因素和健康状况的登记数据。在家访时收集了血液、尿液和环境样本。 迄今为止，已有超过 3,500 名参与者报告诊断为浸润性或原位乳腺癌。 每年都会跟踪该队列的生命状态和主要健康结果的变化。每 2-3 年完成一次关于健康结果、环境和生活方式暴露以及其他主题的详细后续调查问卷。检索癌症和其他优先病症的医疗记录。获得乳腺癌的肿瘤组织。第一个姐妹研究跟踪调查于 2012 年 6 月完成，回复率为 95%。第二次和第三次详细跟踪调查已完成，答复率超过 92%。第四个项目于 2017 年 10 月推出，截至 2019 年 7 月已有 85% 的人做出回应。 我们对饮食因素和乳腺癌风险进行了多项研究。一项研究未能证实先前报道的雌激素相关饮食与乳腺癌之间的联系。在另一项研究中，我们观察到高度坚持“控制高血压饮食方法”(DASH) 饮食与降低乳腺癌风险相关。遵守替代健康指数也与降低乳腺癌风险有关。我们还发现，饮食依赖酸负荷高的女性比酸负荷低的女性患乳腺癌的风险更大。这表明酸负荷减少的饮食，例如富含水果和蔬菜并因此富含钾盐的饮食，可以预防乳腺癌。此外，我们发现，增加红肉的摄入量与浸润性乳腺癌的风险增加有关，而结果表明，用家禽代替红肉可以降低乳腺癌的发病率。 在关于肥胖风险因素的三项研究中的第一项中，我们发现与不规律吃早餐（每周 3-4 天）的女性相比，每天早上吃早餐的女性肥胖的可能性较小。接下来，我们发现长期使用青霉素可能与肥胖风险增加有关。最后，我们观察到，晚上睡觉时暴露在人造光下与超重或肥胖有关，其中与那些报告房间里开着灯或电视的人有更强的关联。 2014-15 年，我们重复收集了自入组以来诊断为乳腺癌的女性的生物和环境样本以及人体测量数据，并随机抽取了未患乳腺癌的女性样本。在受邀的约 3,800 名参与者中，从 2,436 名（63%）人身上采集了样本，其中包括 1,229 名被诊断患有乳腺癌的女性。到目前为止，我们已经发表了三项利用两次收集的生物样本的研究。首先，我们评估了基线和 2014-15 年从脚趾甲中收集的 16 种微量元素的浓度，发现含量通常随着时间的推移而下降，特别是镉、铬和铅。我们利用这些结果更好地为微量元素和年轻发病乳腺癌的研究提供信息，在校正病例与对照收集年份的差异后，没有发现任何测量元素之间存在关联的证据。在另一项研究中，我们观察到，虽然乳腺癌病例和非乳腺癌病例的血清 25-羟基维生素 D 浓度平均较高，但与第一个时间点相比，在第二个时间点，病例的增加幅度更大。最后，我们研究了随着时间的推移，乳腺癌幸存者是否比未患乳腺癌的女性更有可能出现心血管疾病危险因素（例如高血压、高胆固醇、超重），但没有发现差异。 作为多站点乳腺癌协会联盟和卵巢癌协会联盟的一部分，截至 2014 年的乳腺癌和卵巢癌病例以及队列的随机样本已进行基因分型。通过这些项目，姐妹研究数据已被纳入多项合作分析中，包括：预测 DNA 甲基化和乳腺癌的研究；预测 DNA 甲基化和卵巢癌的研究；维生素 D 相关基因与卵巢癌的研究；抗苗勒管激素 (AMH) 水平的全基因组关联研究 (GWAS)；六种实体瘤癌症的 GWAS；关于肥胖、胰岛素、葡萄糖和乳腺癌的孟德尔随机研究；以及多基因风险评分、乳腺癌和乳腺癌亚型的研究。 我们还领导或正在为其他几个联盟项目做出贡献，包括与主要合作者 Hazel Nichols（北卡罗来纳大学）、Anthony Swerdlow 和 Minouk Schoemaker（英国癌症研究所）合作的绝经前乳腺癌合作项目。迄今为止，已有 20 多个团体加入了这项工作。在去年发表的一篇论文中，我们表明较高的体重指数与降低绝经前乳腺癌的风险相关。我们还发现，与未生育的女性相比，生育过的女性患乳腺癌后不久的风险会增加；直到分娩后 20 多年，分娩才会对乳腺癌产生保护作用。其他联盟的项目包括一项关于镇痛剂使用和卵巢癌的研究、一项关于 AMH 和乳腺癌风险预测的研究，以及两项关于胆道癌风险因素的研究。 亚历山德拉·怀特 (Alexandra White) 博士领导了利用公开数据集观察参与者估计接触空气有毒物质的情况来确定乳腺癌环境风险因素的工作。我们发现，生活在空气中镉、铅和汞含量较高地区的女性患绝经后乳腺癌的风险较高。其他空气污染物，包括二氯甲烷、二氯丙烷、多环有机物和苯乙烯，与乳腺癌风险较高有关。怀特博士最近获得了女性健康研究办公室的一笔资助，用于研究微量元素（在脚趾甲样本中测量）与乳腺癌风险的关系。此外，我们还与 Joel Kaufman 博士（华盛顿大学）合作研究标准空气污染物和乳腺癌，一项新的合作在姊妹研究中考虑了空气污染和心血管疾病之间的关联，这项工作将扩大到包括乳腺癌。 在 Jack Taylor 博士领导的一项计划中，我们之前为基因分型样本中的非西班牙裔白人女性生成了 450,000 个 CpG 数据。我们现在已经报告了数千个与乳腺癌风险相关的部位，其中许多可能有助于检测早期浸润性乳腺癌。我们还确定了与饮酒和母亲出生年龄相关的 CpG。我们最重要的贡献之一是表观遗传年龄领域，这是一种使用特定 DNA 甲基化标记量化年龄的生物学测量方法。我们观察到三个表观遗传年龄时钟与乳腺癌之间呈正相关。在随后的分析中，我们发现表观遗传年龄与轮班工作和空气污染之间存在关联。泰勒博士小组计划开展一项新的 DNA 甲基化研究，重点关注非裔美国女性和雌激素受体阴性乳腺癌。 钱德拉·杰克逊博士的小组一直在使用姐妹研究数据来研究睡眠的预测因素和健康影响。我们发现经历过童年创伤的女性睡眠质量较差。在另一项研究中，我们发现每晚平均睡眠时间少于 7 小时且难以入睡或保持睡眠状态的女性更有可能患有代谢紊乱。