We carried out a genome-wide association study among Chinese women to identify risk variants for breast cancer. After analyzing 607,728 SNPs in 1,505 cases and 1,522 controls, we selected 29 SNPs for ...a fast-track replication in an independent set of 1,554 cases and 1,576 controls. We further investigated four replicated loci in a third set of samples comprising 3,472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the gene encoding estrogen receptor α (ESR1), showed strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24-1.49) and 1.59 (1.40-1.82), respectively, for genotypes A/G and A/A versus G/G (P for trend 2.0 × 10−15) in the pooled analysis of samples from all three stages. We also found a similar, albeit weaker, association in an independent study comprising 1,591 cases and 1,466 controls of European ancestry (Ptrend = 0.01). These results strongly implicate 6q25.1 as a susceptibility locus for breast cancer.
ObjectivesDuring the last two decades, researchers and funders increasingly recognised the value of engaging patients and communities in research. Despite progress, community engagement remains ...challenging. There are few examples of successful participant engagement in governance of large-scale research programmes. Here we describe efforts to engage participants as partners in new governance roles in the All of Us Research Program, a precision medicine research initiative which intends to enrol at least one million participants. Using intentional, participant-centric engagement strategies, the All of Us Engagement Core recruited and integrated a diverse group of participants into governance roles including Steering and Executive Committees. Evaluation measures included a survey to assess Consortium Members’ readiness for participant engagement.ResultsOver a 3-year period, all items on the survey increased (higher readiness). Of the 291 respondents to the 2021 survey, respondents most frequently agreed that participant perspectives are essential (100%), participants understand enough to contribute meaningfully (94%) and participants should be involved in setting goals (96%). Respondents least frequently agreed that participants should have an equal voice in Working Groups (75%), Steering Committee (69%) and Executive Committee (63%).ConclusionIn conclusion, participants can be effectively integrated into large-scale research governance, which is associated with increased researcher readiness for engagement.
This chapter posits that cancer is a complex and multifactorial process as demonstrated by the expression and production of key endocrine and steroid hormones that intermesh with lifestyle factors ...(physical activity, body size, and diet) in combination to heighten cancer risk. Excess weight has been associated with increased mortality from all cancers combined and for cancers of several specific sites. The prevalence of obesity has reached epidemic levels in many parts of the world; more than 1 billion adults are overweight with a body mass index (BMI) exceeding 25. Overweight and obesity are clinically defined indicators of a disease process characterized by the accumulation of body fat due to an excess of energy intake (nutritional intake) relative to energy expenditure (physical activity). When energy intake exceeds energy expenditure over a prolonged period of time, the result is a positive energy balance (PEB), which leads to the development of obesity. This physical state is ideal for intervention and can be modulated by changes in energy intake, expenditure, or both. Nutritional intake is a modifiable factor in the energy balance-cancer linkage primarily tested by caloric restriction studies in animals and the effect of energy availability. Restriction of calories by 10 to 40% has been shown to decrease cell proliferation, increasing apoptosis through anti-angiogenic processes. The potent anticancer effect of caloric restriction is clear, but caloric restriction alone is not generally considered to be a feasible strategy for cancer prevention in humans. Identification and development of preventive strategies that "mimic" the anticancer effects of low energy intake are desirable. The independent effect of energy intake on cancer risk has been difficult to estimate because body size and physical activity are strong determinants of total energy expenditure. The mechanisms that account for the inhibitory effects of physical activity on the carcinogenic process are reduction in fat stores, activity related changes in sex-hormone levels, altered immune function, effects in insulin and insulin-like growth factors, reduced free radical generation, and direct effect on the tumor. Epidemiologic evidence posits that the cascade of actions linking overweight and obesity to carcinogenesis are triggered by the endocrine and metabolic system. Perturbations to these systems result in the alterations in the levels of bioavailable growth factors, steroid hormones, and inflammatory markers. Elevated serum concentrations of insulin lead to a state of hyperinsulinemia. This physiological state causes a reduction in insulin-like growth factor-binding proteins and promotes the synthesis and biological activity of insulin-like growth factor (IGF)-I, which regulates cellular growth in response to available energy and nutrients from diet and body reserves. In vitro studies have clearly established that both insulin and IGF-I act as growth factors that promote cell proliferation and inhibit apoptosis. Insulin also affects on the synthesis and biological availability of the male and female sex steroids, including androgens, progesterone, and estrogens. Experimental and clinical evidence also indicates a central role of estrogens and progesterone in regulating cellular differentiation, proliferation, and apoptosis induction. Hyperinsulinemia is also associated with alterations in molecular systems such as endogenous hormones and adipokines that regulate inflammatory responses. Obesity-related dysregulation of adipokines has the ability to contribute to tumorigenesis and tumor invasion via metastatic potential. Given the substantial level of weight gain in industrialized countries in the last two decades, there is great interest in understanding all of the mechanisms by which obesity contributes to the carcinogenic process. Continued focus must be directed to understanding the various relationships between specific nutrients and dietary components and cancer cause and prevention. A reductionist approach is not sufficient for the basic biological mechanisms underlying the effect of diet and physical activity on cancer. The joint association between energy balance and cancer risk are hypothesized to share the same underlying mechanisms, the amplification of chemical mediators that modulate cancer risk depending on the responsiveness to those hormones to the target tissue of interest. Disentangling the connection between obesity, the insulin-IGF axis, endogenous hormones, inflammatory markers, and their molecular interaction is vital.
We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide ...association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women ORs (95% CI) = 1.30 (1.22-1.38) and 1.64 (1.50-1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10⁻³⁰, Japanese women ORs (95% CI) = 1.31 (1.13-1.52) and 1.37 (1.06-1.76), P for trend = 2.51 × 10⁻⁴, and European-ancestry American women ORs (95% CI) = 1.07 (0.99-1.16) and 1.18 (1.04-1.34), P for trend = 0.0069. No association with this SNP, however, was observed in African American women ORs (95% CI) = 0.81 (0.63-1.06) and 0.85 (0.65-1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r(2) = 0.91) and European-ancestry (r² = 0.83) populations, but not in Africans (r² = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region.
To understand participant preferences for receiving specific types of research information, whether information preferences vary across sociodemographic groups, and the types of health providers ...participants could access to understand returned information.
All of Us Research Program participants completed a value of returning research information survey. Stratified sampling was implemented to enhance participant diversity and avoid noncoverage. We used weighted multivariable logistic regression to evaluate associations between the most valuable information types, access to providers, and sociodemographic variables.
Participants (N = 20,405) were diverse in their race/ethnicity (eg, 52% were White, 18% were Hispanic/Latino or Spanish, 3% were Asian, and 20% were Black or African American). Most participants (78.6%) valued information about their risk of serious genetic diseases with available treatment. Primary care physicians, specialists, and genetic counselors were the top providers that participants could access for help understanding returned information. Information preferences and provider access varied across sociodemographic groups. For example, as income levels increased, the odds of placing value on genetic results indicating risk of serious disease with available treatment increased when compared with the lowest income levels (P value < .001).
Although genetic information was most valuable to participants, preferences about specific information types varied across sociodemographic groups.
Abstract Background : American women are five times more likely to be at risk for breast cancer than women from Asian countries. Epidemiologic studies have linked energy balance to an increased risk ...of breast cancer, yet few studies have investigated potential mediators of this association with Chinese women. We examined the above association by blood levels of insulin-like growth factors (IGFs), binding proteins, and C-peptide in the Shanghai Breast Cancer Study (SBCS), a case–control study conducted among 1459 breast cancer cases and 1556 healthy Chinese women from 1996 and 1998. Methods : In-person surveys were used to collect data on energy intake, anthropometric measures, exercise/sport activity, and occupational activity. The present analyses consisted of 397 cases and 397 controls whose blood samples were measured for levels of IGFs, insulin growth-factor binding protein 3 (IGFBP-3), C-peptide, and the relationship with physical activity status, total energy intake, and body fat distribution. Results : Body mass index (BMI) and waist-to-hip ratio (WHR) were significantly positively correlated with IGFBP-3 and C-peptide. Adult exercise/sport activity was significantly negatively correlated with insulin-like growth factor 1 (IGF-I). C-peptide levels increased with increasing quartiles of WHR ( p for trend < 0.01). Additional analyses were performed to evaluate whether the association of energy balance measures with breast cancer risk changed after adjustment for IGFs, IGFBP-3, and C-peptide biomarkers. The associations attenuated, but none of them changed substantially. Conclusion : Insulin resistance biomarkers may partially explain the association between positive energy balance and breast cancer risk, but future studies are needed to identify the underlying complex biological mechanisms of action for breast cancer prevention.
Breast cancer remains the most common cancer in women, and screening mammography is the best method for early detection. Approximately 10% to 15% of women undergoing screening mammography have ...abnormal or incomplete findings that require further diagnostic studies. The time to follow up is reported to be between 9 weeks and more than 19 weeks. Evidence indicates that a delay of more than 3 months in women with symptomatic breast cancer is associated with increased rates of breast cancer recurrence and death. The reasons for the delay are varied, and study findings suggest that minority and low-income women experience more delays than other groups do. The results from 22 studies are summarized. The identified barriers to completion of screening mammography were grouped as patient, provider, and system categories. Most of the studies were descriptive, retrospective studies that describe and measure the barriers in varied ways. Patient barriers were the most extensively described barrier, with little attention given to specific provider and system barriers. Women of nonwhite race with lack of insurance emerged as a subgroup that experienced more delay after abnormal or incomplete results. Provider and system barriers are also not well documented, and further exploration of these barriers is also recommended.
Abstract Objectives Recruiting underserved women in breast cancer research studies remains a significant challenge. We present our experience attempting to locate and recruit minority and medically ...underserved women identified in a Nashville, Tennessee public hospital for a mammography follow-up study. Study design The study design was a retrospective hospital-based case–control study. Methods We identified 227 women (88 African-American, 65 Caucasian, 36 other minority, 38 race undocumented in the medical record) who had undergone screening mammography and received an abnormal result during 2003–2004. Of the 227 women identified, 159 women were successfully located with implementation of a tracking protocol and more rigorous attempts to locate the women using online directory assistance and public record search engines. Women eligible for the study were invited to participate in a telephone research survey. Study completion was defined as fully finishing the telephone survey. Results An average of 4.6 telephone calls (range 1–19) and 2.7 months (range 1–490 days) were required to reach the 159 women contacted. Within three contact attempts, more cases were located than controls (61% cases vs. 49% controls, p = 0.03). African-American women cases were four times likely to be recruited than African-American controls, (OR, 4.07; 95% CI, 1.59–10.30) ( p = 0.003). After 3 months of effort, we located 67% of African-American women, 63% of Caucasian women, and 56% of other minorities. Ultimately, after a maximum of 12 attempts to contact women, 77% of African-American women and 71% of Caucasian women were eventually found. Of these, 59% of African-American women, 69% Caucasian women, and 50% other minorities were located and completed the study survey for an overall response rate of 59%, 71%, and 47% respectively. Conclusions Data collection and study recruitment efforts were more challenging in racial and ethnic minorities. Continuing attempts to contact women may increase minority group study participation but does not guarantee retention or study completion.
Engaging underrepresented groups in outcomes research is a public health priority for reducing health and health care disparities; yet, engaging these groups is challenging. Failure to involve these ...underrepresented populations in research further exacerbates these disparities. This article presents the health and research priorities of diverse groups of underrepresented populations in biomedical research, their concerns for participating in research, and strategies to engage them in their healthcare and research studies. Eleven community listening sessions, ranging from 7 to 13 community members each (N = 117), representing racial/ethnic minority, economically disadvantaged (e. g., uninsured), and hearing impaired communities. We used an inductive, qualitative content analysis approach to analyze the data for emerging themes. We identified the following themes: Uncertainties of underrepresented populations regarding research participation; Ineffective communication about research opportunities and research findings; Research on primary care and prevention are priorities for underrepresented populations in research; and Research teams need training in cultural competence and humility. Underrepresented groups provided research priorities, concerns, and strategies to engage them in their healthcare and in research studies. Findings from this study could facilitate improvement of research participation among underrepresented groups, ultimately reducing health disparities and improving quality of life among groups commonly omitted from research recruitment and participation.
Abstract Vitamin D has been identified as a weak protective factor for postmenopausal breast cancer (relative risk, ~0.9), whereas high breast density has been identified as a strong risk factor ...(relative risk, ~4-6). To test the hypothesis that there is an association between vitamin D intake, but not circulating vitamin D levels, and mammographic breast density among women in our study, we conducted a cross-sectional study of 165 screening mammography patients at Nashville General Hospital's Breast Health Center, a public facility serving medically indigent and underserved women. Dietary and total (dietary plus supplements) vitamin D and calcium intakes were estimated by the Harvard African American Food Frequency Questionnaire, and blood samples were analyzed for 25-hydroxyvitamin D. Average percent breast density for the left and right breasts combined was estimated from digitized films using an interactive thresholding method available through Cumulus software. After statistical adjustment for age, race, and body mass index, the results revealed that there were significant trends of decreasing breast density with increasing vitamin D and calcium intake among premenopausal but not among postmenopausal women. There was no association between serum vitamin D and breast density in premenopausal or postmenopausal women. Confirmation of our findings in larger studies may assist in clarifying the role of vitamin D in breast density.
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