The Two Sister Study

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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.