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

National Institute Of Environmental Health Sciences

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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 blood, urine, and dust samples were collected at in-home visits. The cohort is tracked annually for changes in health. 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 complete (2021-2022) and the 6th will launch in fall 2023. To date, over 4,000 participants have reported a breast cancer diagnosis. Sister Study data were used for a variety of research projects led by Dr. Dale Sandler and other NIEHS investigators (as described below) during 2022-2023. Data are also being used by NIH and other collaborators, and the Sister Study continues to contribute to large collaborative projects. Dr. Sandlers group reported findings on: (1) pregnancy-related and early life risk factors for breast cancer or other chronic diseases, (2) the health impacts of chemical and environmental exposures, and (3) hormones and chronic diseases in women. Goldberg et al. found that a history of a gestational hypertensive disorder was not associated with breast cancer. There was also no association in a pooled study of 6 cohorts. In that study, preterm birth was associated with higher rates of breast cancer only among those who experienced preeclampsia or gestational hypertension. Woo et al. considered latent classes involving 20 types of traumatic experiences (physical or sexual abuse, major accidents, or illnesses, etc.) and telomere length, finding that experiencing high early life trauma was associated with shorter telomere length in adulthood. Ongoing related projects include studies of socioeconomic factors and environmental exposures experienced during childhood and adolescence in relation to long-term health. Using newly collected data on lifetime use of douche and talc in the genital area, Drs. OBrien and Sandler found that participant responses were fairly consistent when asked at different time points, supporting ongoing studies of the association between these products and a variety of hormone-related conditions. Drs. Jing Xu and Sandler reported that exposures to specific components of air pollution from combustion of fossil fuels were positively associated with prevalent hypertension. They also showed that higher neighborhood-level disadvantage was associated with a high prevalence of hypertension. In collaborative studies, residential proximity to green space (tree cover) was associated with a decreased odds of being overweight or obese, US-born Hispanic/Latina women were found to be more likely to have been screened for breast cancer than foreign-born Hispanic/Latina, women with periodontal disease, tooth loss, or both had higher overall mortality rates than women without those conditions, and several measures of obesity and metabolic dysfunction were positively associated with thyroid cancer. Drs. OBrien and Sandler, and summer intern Ms. Sharonda Lovett, showed that bilateral oophorectomy was associated with a lower incidence of breast cancer, both overall and when accompanied by unopposed estrogen hormone therapy. In contrast, hysterectomy without oophorectomy was associated with higher incidence of breast cancer, particularly for women who also took estrogen plus progestin hormones. In work from Dr. Alexandra Whites group, Dr. Che-Jung Chang found that use of hair relaxers was positively associated with uterine cancer incidence. Using publicly available data on industrial emissions at facilities located near participants homes, Dr. White and collaborators found that long-term exposure to airborne dioxin emissions within 3 km of participants residences was associated with increased breast cancer risk. They also found that among non-Hispanic Black women, residential proximity to one or more Superfund sites was associated with higher toenail concentrations of antimony, lead, and cadmium, while antimony and lead were positively associated with Superfund site proximity among non-Hispanic White women. Dr. Marina Sweeney reported that sleeping with a television or light on in the bedroom was associated with a small increase in breast cancer risk although there was no association with ambient nighttime light exposure. Compared to sleeping with no light in the bedroom, sleeping with a TV on was also correlated with several measures of poor sleep health, including shorter sleep duration, inconsistent sleep time, and overall poor sleep scores. Dr. Chandra Jacksons group has led projects showing that women with insomnia and/or short sleep were more likely to develop hypertension and that experiencing discrimination was associated with an increased risk of developing type 2 diabetes. Her team also found that having a traumatic childhood event was associated with a higher risk of type 2 diabetes, with the strongest associations seen among Latina women (64% increase). Drs. Jack Taylor and Jacob Kresovich have led the Sister Study team in investigations of DNA methylation-based markers of age acceleration. Women diagnosed and treated for breast cancer were found to have increased biological aging compared to women who remained free of breast cancer. Further, among women with breast cancer, the association with biological aging was most pronounced for those who received radiation therapy. Drs. Taylor, Kresovich, and Sandler also found that 3 different measures of methylation-based biological age were positively associated with a history of hypertension. Further, among women without hypertension at enrollment, those with higher biological age were more likely to be diagnosed during follow-up. The team also used methylation data to estimate blood immune cell proportions, finding that minor differences in those proportions were associated with later development of hypertension. With former NIEHS investigator Honglei Chen, the team found that by including questions on Parkinsons disease (PD) symptoms and treatments, participants can validly self-report PD and found that air pollution was associated with PD risk. A related paper found little evidence for an association with poor olfaction, a PD prodromal feature. The Sister Study contributed data to large scale research consortia. In the CARRIERS consortium, researchers found that women with breast cancer and mutations in BRCA1, BRCA2, CHEK2, but not ATM were at substantially increased risk of contralateral breast cancer and may benefit from enhanced surveillance and risk reduction strategies. While many studies have separately examined genetic and environmental risk factors for breast cancer, relatively few have considered interactions. In a large study (46,060 cases and 47,929 non-cases total) of women with European ancestry, no strong interactions were identified, except for variants in the C13orf45 gene and age at first full-term pregnancy. In another pooled analysis, investigators examined whether the number of copies of specific genetic markers (copy number variants or CNVs) is related to risk of ovarian cancer. CNVs at established breast and ovarian cancer-related genes, including BRCA1, RAD51C and BRCA2 were associated with ovarian cancer risk, as were 4 rare CNVs in novel locations. In an evaluation of aspirin use and ovarian cancer, researcher found that aspirin use was associated with reduced risk only among women with two or more risk factors, suggesting that the use of aspirin for ovarian cancer chemoprevention may best be targeted to women with multiple risk factors.