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

National Institute Of Environmental Health Sciences

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Abstract

As described in our recently published methods paper, we are currently following 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 of women who develop breast cancer (or other diseases) and a sample of those who don't. More than 3,000 Sister Study participants have reported an incident diagnosis of invasive or in situ breast cancer to date. 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. Medical records and tumor tissue are retrieved for those who develop cancer or other conditions of interest. The first Sister Study follow-up survey was completed in June 2012; responses were obtained from 48,090 women for a response rate of 95%. The second (01/2012 to 07/2014) and third (09/2014 to 08/2016) detailed follow-up surveys was completed with better than 92% response. A new follow-up effort began in October 2017, with a 90% response rate through August 2018. In 2014-15 we repeated the collection of biological and environmental samples from women diagnosed with breast cancer since enrollment and a random sample of the cohort. Of approximately 3,800 participants invited, samples were collected from 2,436 (63%) including 1,229 women who had been diagnosed with breast cancer. Repeat samples will allow us to explore changes in biomarkers and exposures over time and in relation to breast cancer diagnosis and treatment. So far, we have published one study (with others submitted) that made use of twice-collected biospecimens. Here, 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. In summer 2017 we began contacting participants to obtain comprehensive updates on family history of cancers relevant to breast cancer risk prediction. Currently 86% of participants have responded to this survey. Additionally, beginning in December 2017 we started requesting mammography records from a sample of participants so that we can incorporate changes in breast density to improve risk prediction models (collaborators Parisa Tehranifar and Mary Beth Terry from Columbia University). This will enable future work on environmental contributors to breast density, a marker of increased breast cancer risk. In the spring of 2018 we began mailing smell tests to a sample of participants identified for a study of air pollution and loss of sense of smell (collaborator Honglei Chen, Michigan State University). 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 data have been included in several collaborative analyses, including two recent transcriptome-wide association studies and studies of potentially novel loci for overall or estrogen-receptor-negative breast cancer. We also previously generated data on 450,000 CpGs for the non-Hispanic white women in the genotyping sample. We are evaluating methylation patterns in relation to breast cancer and to various exposures of interest. The first such analysis to be published is a study of vitamin D, DNA methylation and breast cancer. Analyses of the associations between DNA methylation and breast cancer and DNA methylation and alcohol use are currently under review. Additionally, we are leading a Consortium project on premenopausal breast cancer - The Premenopausal Breast Cancer Collaboration - with primary collaborators Hazel Nichols (University of North Carolina) and Anthony Swerdlow and Minouk Schoemaker (Institute for Cancer Research in the UK). To date more than 20 cohorts have joined this effort. In a paper published this year, we showed that higher BMI was associated with reduced risk of premenopausal breast cancer risk. A paper on recent pregnancy and premenopausal breast cancer risk is forthcoming, and we have additional projects in the pipeline. Our collaboration with researchers from the Division of Cancer Prevention and Control at the Centers for Disease Control and Prevention to study quality of life in breast cancer survivors continues. A survey of approximately 20,000 Sister Study participants in 2012 focused on the impact of having a sister with breast cancer. A second survey, completed in May 2013, involved women diagnosed with breast cancer and included topics that are of interest to younger women such as body image, work-life balance, and fertility. We recently published an analysis of the research question that originally motivated our CDC collaboration, namely how communication with providers and other trusted relationships contributes to how mothers talk to their daughters about breast cancer risk. In addition to the grant funding acquired by Drs. Chen and Tehranifar, a third extramural collaborator, Dr. Joel Kaufman, has received grant funding for work building on the Sister Study and other cohorts. Dr. Kaufman is leading research on air pollution and cardiovascular disease. As part of this research we will be medically validating some types of cardiovascular disease and acquiring updated geocoding and air pollution exposure estimates. Recent findings from the Sister Study concern early life and more recent environmental and lifestyle exposures. For example, we reported that childhood pesticide exposure was associated with increased risk of rheumatoid arthritis and that childhood residence on or near heavily travelled roads was associated with a small increase in breast cancer risk. We additionally showed that frequent use of beauty products or skincare products was associated with increased breast cancer risk, and that several novel measures of poor sleep were also associated with increased breast cancer risk. Dr. Chandra Jackson's group has been using Sister Study data to study poor sleep as a risk factor for or outcome of other factors, including a study of how exposure to traumatic childhood experiences may contribute to poor sleep in adulthood (in review), and forthcoming papers on the relationship between sleep, type II diabetes, and obesity. Additionally, Dr. Jackson was recently awarded a grant to study metabolomics and type II diabetes in African-American women. In collaboration with Dr. Clarice Weinberg and her team, we previously observed an inverse association between high levels of serum 25-hydroxyvitamin D and breast cancer risk. Following-up on this work, we reported that single nucleotide polymorphisms in vitamin D-related genes may modify vitamin D-breast cancer associations. In a genome-wide association study, we identified two loci associated with serum 25-hydroxyvitamin D levels. We have conducted several studies of dietary factors and their relationship with breast cancer risk. A paper in press failed to confirm a previously reported link between an estrogen-related diet and breast cancer. In the first of three obesity-related studies, we showed that a pro-inflammatory diet was associated with increased risk of all-cause and cardiovascular disease mortality in metabolically unhealthy, overweight or obese women. In the second study, we showed that women who lived near green areas were less likely to be obese and more likely to have high physical activity levels.