Jasmine A. McDonald

Long-Term Reactions to Genetic Testing for BRCA1 and BRCA2 Mutations: Does Time Heal Women's Concerns?

PURPOSE Short-term reactions to BRCA1 and BRCA2 (BRCA1/2) genetic test results have been described in several reports, but the long-terms effects of testing have not been examined extensively. METHODS We conducted an observational study to characterize the long-term impact of genetic testing for BRCA1/2 mutations in 167 women who had received genetic test results at least 4 years ago. We also evaluated the relationship between genetic testing-specific reactions and breast and ovarian cancer screening to determine the behavioral significance of adverse reactions. RESULTS Seventy-four percent of women were not experiencing any distress regarding their test result, 41% were not experiencing any uncertainty, and 51% had a score for positive experiences that was suggestive of low levels of adverse reactions in terms of family support and communication. Mutation carriers (odds ratio, 3.96; 95% CI, 1.44 to 10.89; P = .01) were most likely to experience distress. Only less time since disclosure was related significantly to experiencing uncertainty (odds ratio, 0.62; 95% CI, 0.44 to 0.88; P = .008). In terms of cancer screening, 81% of women had a mammogram during the year before study enrollment, 25% had magnetic resonance imaging (MRI), 20% had a transvaginal ultrasound, and 20% had a CA-125. Experiencing distress was associated significantly with having a CA-125 (χ(2) = 3.89, P = .05), and uncertainty was associated with having an MRI (χ(2) = 8.90, P = .003). CONCLUSION Our findings show that women are not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease.

Dietary Modifications, Weight Loss, and Changes in Metabolic Markers Affect Global DNA Methylation in Hispanic, African American, and Afro-Caribbean Breast Cancer Survivors

BACKGROUND Lower levels of global DNA methylation in tissue and blood have been associated with increased cancer risk. Conversely, cross-sectional analyses of healthier lifestyle patterns have been associated with higher levels of global DNA methylation. OBJECTIVE In this trial, we explored the associations between changes in lifestyle modifications (diet, weight loss), metabolic markers, and global epigenetic biomarkers in white blood cells. METHODS Study participants were Hispanic, African American, and Afro-Caribbean overweight and sedentary female breast cancer survivors (n = 24) who participated in a larger randomized, crossover, pilot study of a 6-mo weight loss intervention and who had available blood specimens. Anthropometric measures, a food-frequency questionnaire, and peripheral blood were collected at baseline, 6 mo, and 12 mo. Plasma samples were analyzed for metabolic markers (insulin, glucose). We measured DNA methylation of long interspersed nucleotide element 1 (LINE-1) and satellite 2 by pyrosequencing and MethyLight, respectively, and global DNA methylation by the luminometric methylation assay (LUMA). RESULTS DNA methylation of LINE-1 was statistically significantly elevated at 6 mo [75.5% vs. 78.5% (P < 0.0001)] and 12 mo [75.5% vs. 77.7% (P < 0.0001)], compared to baseline. Over a 12-mo period, changes in percentage body fat and plasma glucose concentrations were positively associated with LINE-1 DNA methylation (β = 0.19, P = 0.001) and LUMA DNA methylation levels (β = 0.24, P = 0.02), respectively. Similarly, 12-mo changes in dietary measures such as vegetable (β = 0.009, P = 0.048), protein (β = 0.04, P = 0.001), and total caloric (β = 0.05, P = 0.01) intake were positively associated with changes in LUMA DNA methylation, as was intake of fruit positively associated with changes in LINE-1 DNA methylation (β = 0.004, P = 0.02). CONCLUSIONS Our hypothesis-generating results suggest that lifestyle modifications may be associated with changes in global DNA methylation detectable at 6 and 12 mo. These biomarkers may be useful intermediate biomarkers to use in future intervention trials. This trial was registered at clinicaltrials.gov as NCT00811824.

Intentions to Donate to a Biobank in a National Sample of African Americans

Background/Aims: Despite the investments being made to develop biobanks, African Americans are under-represented in genomic studies. We identified factors having significant independent associations with intentions to donate personal health information and blood and/or tissue samples to a biobank in a national random sample of African Americans (n = 1,033). Methods: We conducted a national survey from October 2010 through February 2011. Results: Twenty-three percent of respondents reported that it was not at all likely that they would donate to a biobank, 18% reported it was a little likely, 36% reported it was somewhat likely, and 23% reported it was very likely. Respondents who were likely to donate to a biobank had greater positive expectations about participating in cancer genetics research and reported more participation facilitators relative to barriers. Respondents who were distrustful of researchers had a significantly lower likelihood of being willing to donate to a biobank compared to those who were less distrustful. Conclusions: African Americans have diverse attitudes about participating in genetics research, and many are likely to donate to a biobank based on expectations of positive outcomes. It may be important to address attitudes about genetics research as part of recruitment to enhance the quality of informed consent for participation in biobanks among African Americans.

Epigenetic Biomarkers of Breast Cancer Risk: Across the Breast Cancer Prevention Continuum

Epigenetic biomarkers, such as DNA methylation, can increase cancer risk through altering gene expression. The Cancer Genome Atlas (TCGA) Network has demonstrated breast cancer-specific DNA methylation signatures. DNA methylation signatures measured at the time of diagnosis may prove important for treatment options and in predicting disease-free and overall survival (tertiary prevention). DNA methylation measurement in cell free DNA may also be useful in improving early detection by measuring tumor DNA released into the blood (secondary prevention). Most evidence evaluating the use of DNA methylation markers in tertiary and secondary prevention efforts for breast cancer comes from studies that are cross-sectional or retrospective with limited corresponding epidemiologic data, raising concerns about temporality. Few prospective studies exist that are large enough to address whether DNA methylation markers add to the prediction of tertiary and secondary outcomes over and beyond standard clinical measures. Determining the role of epigenetic biomarkers in primary prevention can help in identifying modifiable pathways for targeting interventions and reducing disease incidence. The potential is great for DNA methylation markers to improve cancer outcomes across the prevention continuum. Large, prospective epidemiological studies will provide essential evidence of the overall utility of adding these markers to primary prevention efforts, screening, and clinical care.

Conducting Precision Medicine Research with African Americans

Importance Precision medicine is an approach to detecting, treating, and managing disease that is based on individual variation in genetic, environmental, and lifestyle factors. Precision medicine is expected to reduce health disparities, but this will be possible only if studies have adequate representation of racial minorities. Objective It is critical to anticipate the rates at which individuals from diverse populations are likely to participate in precision medicine studies as research initiatives are being developed. We evaluated the likelihood of participating in a clinical study for precision medicine. Design, Setting, Participants Observational study conducted between October 2010 and February 2011 in a national sample of African Americans. Main Outcome Measure Intentions to participate in a government sponsored study that involves providing a biospecimen and generates data that could be shared with other researchers to conduct future studies. Results One third of respondents would participate in a clinical study for precision medicine. Only gender had a significant independent association with participation intentions. Men had a 1.86 (95% CI = 1.11, 3.12, p = 0.02) increased likelihood of participating in a precision medicine study compared to women in the model that included overall barriers and facilitators. In the model with specific participation barriers, distrust was associated with a reduced likelihood of participating in the research described in the vignette (OR = 0.57, 95% CI = 0.34, 0.96, p = 0.04). Conclusion and Relevance African Americans may have low enrollment in PMI research. As PMI research is implemented, extensive efforts will be needed to ensure adequate representation. Additional research is needed to identify optimal ways of ethically describing precision medicine studies to ensure sufficient recruitment of racial minorities.

Donation intentions for cancer genetics research among African Americans.

AIMS Scientific agencies rely on individuals to donate their DNA to support research on chronic conditions that disproportionately affect African Americans; however, donation is variable in this population. The purpose of this study was to identify sociodemographic characteristics, health care variables, and cultural values having significant independent associations with intentions to donate blood or saliva samples for cancer genetics research among African American adults. METHOD Cross-sectional survey of donation intentions. RESULTS The majority of respondents (73%) were willing to donate a biological sample for cancer genetics research. The results of the multivariate regression model found that respondents who received care at a facility other than a doctors office (e.g., community center) were about five times more likely to be willing to donate a sample for cancer genetics research (odds ratio [OR]=5.28, 95% confidence interval [CI]=1.16-24.12, p=0.03); whereas, greater levels of religiosity (OR=0.09, 95% CI=0.01-0.75, p=0.02) and present temporal orientation (OR=0.23, 95% CI=0.06-0.79, p=0.02) were associated with a lower likelihood of donating a sample. CONCLUSION Efforts to enhance donation of biological samples for cancer genetics research may need to target diverse clinical sites for recruitment. Additionally, recruitment materials may need to address cultural values related to religiosity and present temporal orientation.

Psychosocial adjustment in school-age girls with a family history of breast cancer

OBJECTIVE: Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study. METHODS: Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH–), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer–specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds). RESULTS: BCFH+ girls had better general psychosocial adjustment than BCFH– peers by maternal report. Psychosocial adjustment and health behaviors did not differ significantly by self-report among 10- to 13-year-old girls. BCFH+ girls reported higher breast cancer–specific distress (P = .001) and were more likely to report themselves at increased breast cancer risk than BCFH– peers (38.4% vs 13.7%, P < .001), although many girls were unsure of their risk. In multivariable analyses, higher daughter anxiety was associated with higher maternal anxiety and poorer family communication. Higher daughter breast cancer–specific distress was associated with higher maternal breast cancer-specific distress. CONCLUSIONS: Although growing up in a family at risk for breast cancer does not negatively affect general psychosocial adjustment among preadolescent girls, those from breast cancer risk families experience greater breast cancer–specific distress. Interventions to address daughter and mother breast cancer concerns and responses to genetic or familial risk might improve psychosocial outcomes of teen daughters.

Maternal cigarette smoking during pregnancy and offspring DNA methylation in midlife

ABSTRACT Maternal smoking in pregnancy (MSP) has been associated with DNA methylation in specific CpG sites (CpGs) in infants and children. We investigated whether MSP, independent of own personal active smoking, was associated with midlife DNA methylation in CpGs that were previously identified in studies of MSP-DNA methylation in children. We used data on MSP collected from pregnant mothers of 89 adult women born in 1959–1964 and measured DNA methylation in blood (granulocytes) collected in 2001–2007 (mean age: 43 years). Seventeen CpGs were differentially methylated by MSP, with multiple CpGs mapping to CYP1A1, MYO1G, AHRR, and GFI1. These associations were consistent in direction with prior studies (e.g., MSP associated with more and less methylation in AHRR and CYP1A1, respectively) and, with the exception of AHRR CpGs, were not substantially altered by adjustment for active smoking. These preliminary results confirm prior prospective reports that MSP influences the offspring DNA methylation, and extends the timeframe to midlife, and suggest that these effects may persist into adulthood, independently of active smoking.

Infection and pubertal timing: a systematic review.

The decline in age of pubertal timing has serious public health implications ranging from psychosocial adjustment problems to a possible increase in reproductive cancers. One biologically plausible explanation for the decline is a decrease in exposures to infections. To systematically review studies that assess the role of infection in pubertal timing, Medline, Web of Science and EMBASE were systematically searched and retrieved studies were reviewed for eligibility. Eligible studies examined the association between infections, including microbial exposures, and physical pubertal characteristics (breast, genitalia and pubic hair development) or age at menarche. We excluded studies that were published in a language other than English, focused on precocious puberty, were case studies, and/or included youth with autoimmune diseases. We report on study design, population characteristics, measurement of infection and puberty and the main effects of infection on pubertal development. Based on our search terms we identified 1372 unique articles, of which only 15 human and five animal studies met our eligibility criteria. Not all studies examined all outcomes. Infection was associated with later breast development (4/4 human studies), with less consistent evidence for genitalia and pubic hair development. Seven studies assessed age at menarche with inconsistent findings (three supporting later, four no association). We conclude that a small but consistent literature supports that infection is associated with later breast development; the evidence for other pubertal events and age at menarche is less clear. Where fewer childhood infections coincide with the rise in incidence of hormone-related cancers.

Adherence to Cancer Prevention Guidelines in 18 African Countries

Background Cancer rates in Africa are projected to double by 2030 due to aging and increased exposure to cancer risk factors, including modifiable risk factors. We assessed adherence to 5 modifiable cancer risk factors across 18 African countries. Methods Data on adults 18 years and older were obtained from the 2002–2004 World Health Survey. Adherence to current World Cancer Research Fund guidelines on smoking, alcohol, body weight, physical activity, and nutrition was assessed. Adherence scores ranged from 0 (no guideline met) to 5 (all guidelines met). Determinants of adherence were assessed using multivariable linear regression adjusted for individual and country level characteristics. Results Across all countries, adherence to the guidelines among adults was high for smoking (72%–99%) and alcohol (85%–100%), but low for body weight (1.8%–78%), physical activity (3.4%–84%) and nutrition (1.4%–61%). Overall adherence score ranged from 2.32 in Mali to 3.72 in Comoros. In multivariable models, residing in low versus high SES households was associated with reduced adherence by 0.24 and 0.21 points for men and women respectively after adjusting for age, gender, education, and marital status (p<0.001). Every % increase in GDP spent on health was associated with increased adherence by 0.03 in men and 0.09 in women (p<0.001). Conclusions The wide variation in adherence to cancer prevention guidelines observed across countries and between population sub-groups suggests the need for targeted public health efforts to improve behaviors related to body weight, physical activity and nutrition.