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

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

We are following 50,884 US women who were aged 35-75 and breast cancer free but had a sister previously diagnosed with breast cancer when they enrolled in 2003-2009. Data on potential risk factors and health were collected in computer-assisted telephone interviews. Anthromopetric and blood pressure measurements, and blood, urine, and dust samples were collected at in-home visits. To date, nearly 4,000 participants have reported a breast cancer diagnosis. The cohort is tracked annually for changes in health. Detailed follow-up questionnaires are completed every 3 years. Medical records are retrieved for cancers and other priority conditions. Tumor tissue is obtained for breast and ovarian cancers. Four follow-up surveys have been completed with response rates near 90%. A 5th began in fall 2020, along with a COVID19-related questionnaire. Sister Study research focuses on breast cancer and a range of other conditions through studies within the cohort and consortia efforts that pool data from multiple cohorts. In 2020-2021, Sister Study investigators contributed data and expertise to a large number of collaborative projects. Drs. OBrien and Sandler led two pooled studies on genital powder use and cancer. The first reported a small positive but not statistically significant association between genital powder use and ovarian cancer, with a stronger association among those with intact reproductive tracts. In a related effort, we found no association between genital powder use and uterine cancer. Other ovarian cancer consortium papers showed that established risk factors did not vary by anatomic site (ovary, fallopian tube, peritoneum) and that lifetime number of ovulatory cycles is positively associated with risk. Sister Study investigators co-lead the Premenopausal Breast Cancer Collaborative Group, which reported that gaining weight was associated with a lower risk of premenopausal breast cancer. Dr. O'Brien co-first authored a paper showing that gestational diabetes is not associated with increased risk of young-onset breast cancer. We also contributed to studies of biliary tract and thyroid cancers, some COVID-related initiatives, and various genetic projects. We are collaborators in the CARRIERS consortium, which examined the prevalence and impact of breast cancer predisposition genes in women not selected for high familial risk, in Black women, and in women >age 65. These findings have implications for targeted screening. We also contribute to the BCAC consortium, which published on gene-by-environment interactions, polygenic risk scores, and differences in genetic factors by race/ethnicity. Within the Sister Study, we continue to consider early life factors that may influence breast cancer risk. Drs. Goldberg and Sandler reported that earlier age at thelarche and earlier age at menarche were each associated with increased breast cancer risk, and that experiencing both together had an even greater impact. Dr. Woo studied the role of early life trauma and the risk of breast cancer in adulthood, applying novel approaches to identify what patterns and combinations of abuse might be most strongly associated with risk. With Dr. Weinberg's team, we showed in the Two Sister Study that having a mother with pre-eclampsia was associated with increased risk of developing young-onset breast cancer; this finding is being re-assessed in the main Sister Study cohort. We continue to focus on identifying chemical and environmental risk factors for breast cancer and other conditions. Dr. Whites group led a study of adolescent hair product use and breast cancer, reporting that frequent use of straighteners and perms may be associated with increased premenopausal breast cancer risk. Frequent use of hair straighteners/relaxers (>4 times/year) was associated with twice the risk of ovarian cancer compared to never use. These findings are particularly relevant for Black/African American women, who are more likely to use straighteners/relaxers. Several Sister Study manuscripts have considered the health effects of metals, either measured directly in participant-provided toenail clippings or blood samples, or based on EPA-modeled air toxicant estimates. For example, Dr. Sandler's group found that certain airborne metals were positively associated with prevalent hypertension. Airborne metal exposures were also found to be associated with breast cancer, menopausal status and obesity. Many of these analyses considered the role racial/ethnic disparities in exposure and the importance of considering metals as mixtures, using quantile g-computation and other state-of-the-art statistical methods to address these complex research questions. Another major area of focus has been on the health effects of diet and supplement use. Drs. Sandler and Park found that diets with high pro-inflammatory and pro-oxidative scores were positively associated with breast cancer risk. Tea consumption was inversely associated with breast cancer risk. Red meat was positively associated with breast cancer, whereas poultry intake was inversely associated. Processed red meats were predictive of colorectal cancer risk. Irregular breakfast eating patterns seemed to be associated with increased risk for becoming obese. Most recently, in an analysis of Vitamin D supplement use and breast cancer incidence, Dr. O'Brien led research showing that recent but not ever vitamin D supplement use was associated with decreased breast cancer risk, with no clear differences across racial/ethnic groups, despite disparities in supplement use. In an ongoing project, we are examining the association between vitamin D supplement use and COVID-19 infection and severity. Drs. Park and Sandler led a study of the association between type II diabetes and breast cancer risk, with special consideration for the role of metformin use. We found that while type 2 diabetes may increase the risk of developing breast cancer, metformin appears to counteract the breast cancer related hazards of long-term metabolic changes associated with type 2 diabetes, especially for estrogen receptor-positive breast cancer. Drs. Taylor and Kresovich led the Sister Study team in several DNA methylation studies, including investigations of epigenetic markers of age acceleration and health-related factors. We found that several measures of body size and physical activity, but not alcohol use, were associated with epigenetic age. Most recently, Dr. Kresovich developed a methylation-based predictor of breast cancer. Dr. Lawrence led analyses showing that Sister Study participants from neighborhoods with higher deprivation tended to have epigenetic profiles indicative of more rapid aging. Other efforts that consider social factors and health have been led by Dr. Chandra Jacksons group. We showed that perceived job discrimination was associated with poor sleep, as were traumatic childhood events. Poor sleep was, in turn, associated with incident hypertension. Major racial discrimination was associated with an increased risk of type II diabetes. To increase our ability to study racial disparities in environmental exposures and health, we initiated several overlapping biomarker studies that oversample Black/African-American or Hispanic/Latina women. This includes an assessment of more than 850,000 DNA methylation sites in Black women with and without breast cancer, a study of the human metabolome and type 2 diabetes, a study of metals measured in toenails and breast cancer, a study of circulating vitamin D concentrations and breast cancer in Black and Hispanic women, a collaborative study (William Funk, PI) of adductomics and breast cancer , and additional studies of inherited genetic markers and risk of breast and other cancers via NCIs CONFLUENCE project.