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. Anthropometric and blood pressure measurements, and biological samples were collected at in-home visits. To date, over 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%. The 5th detailed follow-up is underway. Data collected from Sister Study participants were used for a variety of research projects during 2021-2022. Many of these were overseen by Dr. Dale Sandler directly, but investigators from NIEHS (Drs. Alexandra White, Clarice Weinberg, Chandra Jackson, or Jack Taylor) or other NIH institutions (Dr. Emily Vogtmann, NCI; Dr. Faustine Williams, NIMHD) have also led studies. The Sister Study continues to contribute to large collaborative projects, such as the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium and the Breast Cancer Association Consortium (BCAC). Dr. Sandler's group has recently been focused on early life risk factors for breast cancer. Woo et al. reported that about half of all Sister Study participants had at least one traumatic life experience before age 18 and that sexual trauma and household dysfunction or medium levels of early-life trauma were associated with greater risk of developing breast cancer compared to experiencing low levels of early-life trauma. After previously demonstrating that early thelarche was a risk factor for breast cancer, Drs. Sandler and Mandy Goldberg studied what factors influence thelarche, finding that maternal gestational hypertensive disorder, diethylstilbestrol use, smoking during pregnancy, being firstborn, and being born to a teenage mother were all associated with early breast development. There was no association between having a history of a gestational hypertensive disorder and breast cancer in another study. The group also reported that early life socioeconomic disadvantage was independently associated with obesity in adulthood, and not explained by adult socioeconomic factors. Dr. Katie O'Brien has continued to study the association between vitamin D and breast cancer, as well as the potential health effects of genital talc use and douching. In an analysis of Vitamin D supplement use and breast cancer incidence, they found that recent but not ever vitamin D supplement use was associated with lower breast cancer rates, with no clear differences by race/ethnicity. Results from a follow-up study of blood 25-dihyroxyvitamin D (25(OH)D) levels indicated that there may be an inverse association between 25(OH)D and breast cancer among women who self-identify as Black/African American or Hispanic/Latina. Douching during adolescence was weakly positively associated with cervical cancer, but adolescent talc use was not. More recent douching and genital talc use were positively associated with incident cervical cancer. In related work, Drs. O'Brien and Sandler have collaborated with Dr. White to study the potential health effects of certain types of hair products, finding that frequent use of hair straighteners/relaxers was associated with twice the risk of ovarian cancer compared to never use. Dr. White's group has continued to investigate environmental risk factors for breast cancer. They found that high levels of radioactive isotopes and low levels of ultraviolet radiation were associated with higher rates of estrogen receptor negative breast cancer. Air pollution is thought to be associated with overall increased risk of breast cancer, with newly published results indicating that the association may vary by breast cancer family history. Toenail metal concentrations were not associated with breast cancer. Dr. Sandler and Dr. Yong-Moon Park found that diets with high pro-inflammatory and pro-oxidative scores were positively associated with breast cancer risk. Another investigation showed that some carotenoids measured in blood had an inverse association with oxidative stress measures, meaning that they may have antioxidant effects. Others were inversely associated with both inflammation and oxidative stress measures. -carotene supplements, but not dietary carotenoid estimates, were associated with lower levels of inflammation and oxidative stress. Many of the Sister Study's cross-institutional collaborations have sought to understand how sociocultural factors affect health. This included a study showing that higher neighborhood-level disadvantage was associated with a high prevalence of hypertension (Dr. Sandler with Dr. Jing Xu, Peking Union Medical College), that having more tree cover was associated with a decreased odds of being overweight or obese (Dr. Wei-Lun Tsai, Environmental Protection Agency), and that US-born Hispanic/Latina women were more likely to have been screened for breast cancer than foreign-born Hispanic/Latina women (Dr. Williams, NIMHD). A joint NIEHS/NCI collaboration reported that women with periodontal disease, tooth loss, or both had higher overall mortality rates than women without those conditions (Dr. Vogtmann, NCI). Dr. Jackson's social and environmental determinants of health equity group has led projects showing that women with insomnia or insomnia plus short sleep were more likely to develop hypertension and that experiencing major discrimination was associated with an increased risk of developing type 2 diabetes. Dr. Weinberg's group reported that a history of gestational diabetes was associated with an increased risk of developing type 2 diabetes, and that this risk remained elevated for more than 35 years after the affected pregnancy. Drs. Taylor and Jacob Kresovich have led the Sister Study team in several DNA methylation studies, including investigations of epigenetic markers of age acceleration and health-related factors. Recently published papers reported on a methylation-based predictor of breast cancer and how certain dietary patterns may be associated with measures of biological aging. In addition to these stand-alone Sister Study projects, the Sister Study contributes data to the CARRIERS consortium, which seeks to examine the prevalence and impact of breast cancer predisposition genes on breast cancer risk. Recent CARRIERS research efforts have focused in on the impact of these pathogenic variants on risk among US Black women, women >65, or for invasive lobular carcinoma. BCAC has considered similar research questions for more common genetic variants, including studies of polygenic risk scores in women of African ancestry and how established risk variants are related to specific breast cancer subtypes. We have also designed several overlapping biomarker studies embedded within the Sister Study that oversample Black/African American or Hispanic/Latina women, with the aim of being able to better study racial disparities within the cohort. The first two projects, which considered breast cancer and (1) toenail metals (2) vitamin D, have been published. Ongoing work includes an assessment of 850,000 DNA methylation sites in Black women with and without breast cancer, a study of the human metabolome and type 2 diabetes, a collaborative study (William Funk, PI) of adductomics and breast cancer, and many additional studies of inherited genetic markers and risk of breast and other cancers via NCIs CONFLUENCE project.