The Two Sister Study

正如我们发表的研究概述中所讨论的那样，我们招募了50，884名年龄在35岁至74岁之间的美国和波多黎各女性，她们有一个患有乳腺癌的姐妹，但在2003年至2009年期间参加研究时从未患过乳腺癌。在入组时，通过计算机辅助电话访谈和邮寄问卷收集有关潜在风险因素和当前健康状况的数据。在家庭访视中采集血液、尿液和环境样本，并储存以备将来在巢式研究中使用。超过4,000名姐妹研究参与者报告了浸润性或原位乳腺癌的诊断。每年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特别主题的详细后续调查问卷。我们为那些患有癌症或其他感兴趣的疾病的人检索医疗记录和肿瘤组织。 作为多研究“Oncoarray”项目的一部分，2014年的乳腺癌和卵巢癌病例以及队列的随机样本已经进行了基因分型。通过这个项目，姐妹研究和两个姐妹研究数据已被纳入许多合作分析，包括转录组范围的关联研究。 我的博士后Ann Von Holle完成了一个联合项目，她考虑了BMI在女性更年期过渡期乳腺癌风险中的作用。在与奥布莱恩的合作中，我们最近评估了使用生殖器清洁粉和冲洗与卵巢癌和子宫内膜癌风险之间的关系。 我们之前还生成了基因分型样本中非西班牙裔白色女性的450，000个CpG的数据，并计划评估甲基化模式与相关风险因素的关系。在流行病学分支的博士后工作中（Kresovich等人，发表在《分子肿瘤学》上），我们开发了一种基于甲基化的乳腺癌风险评分。 该评分在测试数据和来自欧洲EPIC研究子研究的独立病例对照数据集中表现非常好。 它提供了一种新的风险因素，显然与任何已知的风险因素（年龄和性别除外）一样强，并且独立于已知的风险因素。在与甲基化相关的其他工作中，我们最近发现，经历乳腺癌诊断和后续治疗的女性显示出加速的甲基化评估生物衰老，特别是如果她们接受过放射治疗。 在与迪亚兹桑塔纳的合作中，我们正在使用姐妹研究数据来研究抑郁症和使用抗抑郁药物与风险的关系，并发现这些药物在美国被广泛使用，似乎与乳腺癌的风险有关。 我们还在评估适用于西班牙裔人口，特别是来自波多黎各的妇女的风险预测方法，希望能够为她们开发更个性化和更好校准的风险评估方法。 我们评估了脚趾甲样本中的金属水平，发现不幸的是，脚趾甲中的铁水平与基于血清的生物标志物相关性很差。 在涉及17种微量元素的测量中，一年中剪指甲的时间与测量的水平相当一致，其中许多在夏末达到峰值。 因此，尽管方便，但如果在流行病学研究中使用脚趾甲，则需要调整采样季节。 我们还在一篇正在审查的论文中评估了铁状态的预测模型。 在与新博士后Wanyu Huang的合作中，我们正在开发一种数学方法来总结基于妊娠史的风险，并将使用姐妹研究队列来评估其在妊娠糖尿病，2型糖尿病和其他结局方面的表现。

As discussed in our published overview of the study, we enrolled 50,884 US and Puerto Rican women who were between the ages of 35 and 74 and had a sister with breast cancer but had never had breast cancer themselves when they joined the study between 2003 and 2009. At enrollment, data on potential risk factors and current health status were collected using computer assisted telephone interviews and mailed questionnaires. Blood, urine, and environmental samples were collected in a home visit and banked for future use in nested studies. More than 4,000 Sister Study participants have 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 special topics are completed every 2-3 years. We retrieve medical records and tumor tissue for those who develop cancer or other conditions of interest. Breast cancer and ovarian cancer cases through 2014 and a random sample of the cohort have been genotyped as part of the multi-study "Oncoarray" project. Through this project, Sister Study and Two Sister Study data have been included in many collaborative analyses, including transcriptome-wide association studies. One consortial project was completed by my post-doc, Ann Von Holle, who considered the role of BMI in relation to risk of breast cancer as women transition through the peri-menopausal years. In work with O'Brien we have recently assessed the association between use of genital talcum powder and douching and risk of ovarian and endometrial cancer. We also previously generated data on 450,000 CpGs for the non-Hispanic white women in the genotyping sample, with plans to evaluate methylation patterns in relation to risk factors of interest. In work with a postdoc in the Epidemiology Branch (Kresovich, et al.,published in Molecular Oncology) we developed a methylation-based risk score for breast cancer. This score performed very well in test data and in an independent case-control data set from a substudy of the European EPIC study. It provides a novel risk factor that is evidently as strong as predictor for breast cancer as any known risk factor (excepting age and sex) and is independent of the known risk factors. In other work related to the methylome we recently found that women who experience a breast cancer diagnosis and subsequent treatment show accelerated methylation-assessed biologic aging, particularly if they had been treated with radiation. In work with Diaz Santana we are using the Sister Study data to study both depression and use of anti-depressant medications in relation to risk and found that those medications, which are widely prescribed in the US, appear to be associated with the risk of breast cancer. We are also evaluating methods of risk prediction as applied to Hispanic populations, in particular to women from Puerto Rico, in hopes that more personalized and better-calibrated risk assessment methods can be developed for them. We have assessed levels of metals in toenail samples and found that unfortunately the iron levels in toenails correlate poorly with biomarkers based on serum. In measures involving 17 trace elements in toenails the time of year at which the clipping was done was quite consistently related to the levels measured, with many showing peaks in late summer. Thus, despite their convenience, season of sampling needs to be adjusted for if toenails are used in an epidemiologic study. We also evaluated predictive models for iron status in a paper now under review. In work with a new postdoc, Wanyu Huang, we are developing a mathematical way to summarize risk based on pregnancy history, and will be using the Sister Study cohort to assess its performance for gestational diabetes, type 2 diabetes, and other outcomes.