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年期间参加研究时自己没有患乳腺癌。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3,000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几个合作分析，包括两个最近的转录组关联研究。1例（Fachel等人）对150个与乳腺癌相关的基因进行了精细定位。 另一个联合项目（Kapoor等人）考虑了乳腺癌多基因风险评分与非遗传性既定风险因素之间的相互作用。在我的前博士后（奥布莱恩等人）领导的其他合作工作中，现在是流行病学分支的科学家，研究了使用会阴粉末与卵巢癌风险的关系。 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。我们最近还使用表观遗传数据来应用最近开发的基于甲基化的生物钟，并了解到生物老化的明显加速可预测乳腺癌的风险（Kresovich等人，在JNCI出版）。免疫细胞谱与表观遗传模式有关，也与乳腺癌有关，基于Kresovich等人最近的工作。 在现已发表的工作中（迪亚兹等人），我们使用两姐妹研究的数据来评估非常早期的生活经历与早期发病（50岁以下）乳腺癌风险的关系，并发现证据表明先兆子痫孕妇的风险增加，特别是当在逻辑模型中调整她们后来是否自己怀孕先兆子痫时。我们现在正在根据预期的姐妹研究进行分析，以跟进这项工作。 在其他工作，现在在新闻（冯霍尔，等）。我们发现了乳腺癌发病年龄的家族聚集性证据，这一发现对筛查和病因学都有意义。我们发现，如果一个姐姐被诊断出患有乳腺癌，那么当她的年龄接近受影响姐姐的年龄时，研究姐姐的风险就会增加，即使发病时间较晚。总的来说，这些研究表明对生命轨迹的早期影响，可能与遗传因素协同作用。 铁是一种对生命至关重要的生长因子，也促进脂质过氧化和活性氧（ROS）的形成。有理由认为铁的状况会影响乳腺癌的风险。高肉类饮食已被证明与风险增加有关，血红素铁（主要来自红肉）的消费可能会推动这种关联。 在与博士后（Ann von Holle）的一个项目中，并根据与明尼苏达大学的合同，我们现在已经测量了血清铁，铁蛋白（一种储存和结合铁的蛋白质，将其与感染性病原体隔离）和转铁蛋白饱和度（另一种储存铁的标志物）嵌套在姐妹研究中的病例队列样本中。我们没有发现预期的与铁超载的联系，但确实观察到非常低的铁储备有明显的保护作用。 我们的一些工作与非癌症终点有关。在一个这样的项目中（Niehoff等人），我们发现几乎没有证据表明接触有毒金属会导致高BMI。 来自姐妹研究的数据也用于肌萎缩侧索硬化症的研究。

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 did not have 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 3,000 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 several collaborative analyses, including two recent transcriptome-wide association studies. One (Fachel, et al.) did fine-mapping of 150 genes related to breast cancer. Another consortial project (Kapoor, et al) considered interactions between a polygenic risk score for breast cancer and non genetic established risk factors. In other collaborative work headed up by my former postdoc (O'Brien, et al.), now a Staff Scientist in the Epidemiology Branch, the use of perineal powder was studied in relation to risk of ovarian 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. We also recently used epigenetic data to apply recently developed methylation-based biologic clocks and learned that evident acceleration in biologic aging is predictive of risk of breast cancer (Kresovich, et al., in press at JNCI). Immune cell profiles are related to the epigenetic patterns and are also related to breast cancer, based on recent work by Kresovich et al. In work now published (Diaz, et al.), we used the Two Sister Study data to assess very early life experiences in relation to risk of young-onset (under age 50) breast cancer and found evidence that women born to a preeclamptic pregnancy were at increased risk, particularly when adjustment is made in the logistic model for whether they had later gestated a preeclamptic pregnancy themselves. We are now following up this work with analyses based on the prospective Sister Study. In other work now in press (von Holle, et al.) we found evidence of familial clustering in the age at onset of breast cancer, a finding with implications for both screening and etiology. We found that if an older sister was diagnosed with breast cancer the risk for the studied sister increased when her age was close to the age of the affected sister, even if that onset was later in life. Taken together, these studies suggest very early influences on a life trajectory, perhaps acting synergistically with genetic factors. Iron is a growth factor that is essential to life and also promotes lipid peroxidation and the formation of reactive oxygen species (ROS). There is reason to think that iron status can influence the risk of breast cancer. High meat diets have been shown to be associated with increased risk, and consumption of heme iron (mainly derived from consumption of red meat) may drive this association. In a project with a postdoc (Ann von Holle) and under a contract with the University of Minnesota, we have now measured serum iron, ferritin (a protein that stores and binds iron, sequestering it from infectious agents) and transferrin saturation (another marker for stored iron) in a case-cohort sample nested within the Sister Study. We did not find the expected association with iron overload, but did observe an evidently protective effect of very low iron stores. Some of our work has been related to non-cancer endpoints. In one such project (Niehoff, et al.), we found little evidence that exposure to toxic metals contributes to high BMI. Data from the Sister Study was also used in a study of amyotrophic lateral sclerosis.