A genome-wide linkage study of mammographic density, a risk factor for breast cancer.

INTRODUCTION: Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD). METHODS: Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel. RESULTS: Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study. CONCLUSIONS: The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer.

Adherence to guidance for prioritizing higher risk groups for breast cancer screening during the COVID-19 pandemic in the Ontario Breast Screening Program: a descriptive study.

BACKGROUND: Breast cancer screening in Ontario, Canada, was deferred during the first wave of the COVID-19 pandemic, and a prioritization framework to resume services according to breast cancer risk was developed. The purpose of this study was to assess the impact of the pandemic within the Ontario Breast Screening Program (OBSP) by comparing total volumes of screening mammographic examinations and volumes of screening mammographic examinations with abnormal results before and during the pandemic, and to assess backlogs on the basis of adherence to the prioritization framework. METHODS: A descriptive study was conducted among women aged 50 to 74 years at average risk and women aged 30 to 69 years at high risk, who participated in the OBSP. Percentage change was calculated by comparing observed monthly volumes of mammographic examinations from March 2020 to March 2021 with 2019 volumes and proportions by risk group. We plotted estimates of backlog volumes of mammographic examinations by risk group, comparing pandemic with prepandemic screening practices. Volumes of mammographic examinations with abnormal results were plotted by risk group. RESULTS: Volumes of mammographic examinations in the OBSP showed the largest declines in April and May 2020 (> 99% decrease) and returned to prepandemic levels as of March 2021, with an accumulated backlog of 340 876 examinations. As of March 2021, prioritization had reduced the backlog volumes of screens for participants at high risk for breast cancer by 96.5% (186 v. 5469 expected) and annual rescreens for participants at average risk for breast cancer by 13.5% (62 432 v. 72 202 expected); there was a minimal decline for initial screens. Conversely, the backlog increased by 7.6% for biennial rescreens (221 674 v. 206 079 expected). More than half (59.4%) of mammographic examinations with abnormal results were for participants in the higher risk groups. INTERPRETATION: Prioritizing screening for those at higher risk for breast cancer may increase diagnostic yield and redirect resources to minimize potential long-term harms caused by the pandemic. This further supports the clinical utility of risk-stratified cancer screening.

Breast-tissue composition and other risk factors for breast cancer in young women: a cross-sectional study.

BACKGROUND: Mammographic density is a heritable quantitative trait and is a strong risk factor for breast cancer in middle-aged and older women. However, little is known about the development of mammographic density in early life. We used MRI to measure the water content of the breast, which provides a measurement of the fibro-glandular content of breast tissue with similar accuracy to mammography, but without the attendant exposure to radiation. METHODS: Between December, 2003, and December, 2007, we recruited 400 young women, aged 15-30 years, and their mothers. We used MRI scans to measure daughters' breast water and fat, and on the same day obtained blood for hormone assays in the follicular phase of the menstrual cycle for each young woman. Mothers underwent mammography (n=356), and a random sample (n=100) also consented to have a breast MRI scan. FINDINGS: In mothers, per cent water-as measured by MRI-was strongly correlated with per cent mammographic density (r=0.85). Per cent water in daughters (median 44.8%) was significantly higher than in mothers (median 27.8%; p<0.0001), and was independently inversely associated with both their age (p=0.04) and weight (p<0.0001), and positively associated with their height (p<0.0001) and their mothers' per cent mammographic density (p<0.0001). Serum growth hormone concentrations, adjusted for covariates, were positively associated with per cent breast water (p=0.001) in a subgroup of young women (n=280) who had not used oral contraceptives within 6 months. INTERPRETATION: Per cent breast water was greatest during the ages when women are most susceptible to breast carcinogens, and was associated with weight, height, and mother's breast-tissue characteristics, and with serum concentrations of growth hormone: a breast mitogen that also mediates postnatal somatic growth. Mammographic density in middle age might partly be the result of genetic factors that affect growth and development in early life. FUNDING: Canadian Breast Cancer Research Alliance.

Neonatal experiences differentially influence mammary gland morphology, estrogen receptor {α} protein levels, and carcinogenesis in BALB/c mice.

Prevention of breast cancer can be achieved with a better understanding of the factors contributing to normal breast development. Because the breast develops postnatally, alterations in the development and lifetime activity of the neuroendocrine system may set up an environment that increases cancer risk. The present study examined how two neonatal experiences over the first 3 weeks of life influence normal and malignant mammary gland development in female BALB/c mice. Following puberty, both brief (15 minutes) and prolonged (4 hours) daily maternal separations of newborn mice accelerated mammary gland development relative to nonseparated mice. Despite similar mammary gland morphologies between mice exposed to these two neonatal separation experiences, only mice exposed to prolonged maternal separation bouts showed a higher incidence and faster onset of mammary tumorigenesis following adulthood carcinogen [7,12-dimethylbenz(a)anthracene] administration. Molecular analysis of estrogen receptor α (ERα) and p53, two proteins that have been implicated in breast cancer, revealed that for mice exposed to prolonged neonatal maternal separation bouts, mammary gland ERα protein levels were upregulated in a transcription-independent manner. On the other hand, p53 expression in mammary glands of adult mice was not differentially influenced by neonatal experiences. Our findings show that chronic, moderate psychosocial stress during the neonatal period increases the expression of ERα protein and promotes mammary tumorigenesis in adulthood.