The Two Sister Study

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

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. The Two Sister Study was developed by identifying members of the cohort whose sister was diagnosed before age 50 and recruiting that young-onset affected sister to provide both questionnaire data and saliva for genetic analyses. The two parents also provided DNA via mail-in saliva kits. This add-on family-based study was funded by Susan G. Komen for the Cure. Breast cancer and ovarian cancer cases through 2014 in the Sister Study 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. That paper has now been published. In work with O'Brien we assessed the association between use of hormone replacement drugs, and risk of young onset (under 55) breast cancer. The combination of oestrogen and progestin (particularly long-term use) was associated with increased risk but use of oestrogen alone showed evidence of protection. We had 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 former postdoc in the Epidemiology Branch (Kresovich, now at the Moffitt Cancer Center) related to the methylome we found that several proteins predicted by the epigenome are related to risk of breast cancer. In work with Diaz-Santana we used the Sister Study data to study both depression and use of anti-depressant medications in relation to risk and found that use of SSRI medications, which are widely prescribed in the US, appears to be associated with reduced risk of breast cancer, particularly among women with a strong family history. 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 developed an empirical Bayes method to summarize risk based on pregnancy history, for predicting recurrence and the occurrence of other outcomes. Applying this new method we have now applied it to data on pregnancy history, as reported at baseline in the Sister Study cohort. In work about to be submitted we found that pregnancy loss predicts its recurrence and also provides an independent risk factor for gestational diabetes and for type 2 diabetes. In work with Von Holle we studied the relationship between iron status and methylation-based biological aging metrics. While higher levels of ferritin were positively associated with accelerated biologic aging the same was not seen for serum iron or percent transferring saturation. We also studied breast cancer in relation to self-reported sedentary time and observed apparent effect modification related to menopausal status, with the positive association seen specifically post-menopause. In work with Olga Basso based on the Sister Study, we found an association between being born to a young mother and serious reproductive system problems, as indicated by hysterectomy prior to age 40. In an ongoing project, which is collaborative with Kevin Gerrish, we are studying the possible association between male-origin microchimerism in the blood and breast, ovarian and endometrial cancer, using specimens from the Sister Study. In other work that is now underway, we have acted on the advice offered at the branch's most recent review by the Board of Scientific Counsellors and undertaken whole genome analysis (through the Broad Institute) for the Two Sister Study, so that we can study possible effects of de novo mutations on risk of breast cancer.