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.

Effect of a low-fat, high-carbohydrate dietary intervention on change in mammographic density over menopause.

We have previously shown that a low-fat dietary intervention for 2 years in women with extensive mammographic density decreased mammographic density to a greater extent than in the control group. Post-hoc analysis indicated that this effect was strongest in women who became postmenopausal during the follow-up period. The purpose of the present study was to determine if this potentially important finding could be confirmed in a new and larger group of subjects with a longer follow-up time. Participants in a low-fat dietary intervention trial who were premenopausal at entry and became postmenopausal during follow-up were examined. Total breast, dense, and non-dense area and percent density were measured in baseline and postmenopause mammograms using a computer-assisted method. Total breast and non dense area increased more in the control group compared to the intervention group (for breast area 2.6 and 0.2 cm(2), respectively; P=0.05, and for non-dense area 10.9 and 8.1 cm(2), respectively; P=0.06). Dense area decreased to a similar degree in both groups (-8.2 and -8.0 cm(2), respectively; P=0.84). Percent density decreased to a slightly greater degree in the control compared to intervention group (-9.4 and -7.8%, respectively, P=0.11). There were no significant differences between study groups after adjustment for weight change. Menopause reduced density to a similar extent in the low-fat diet and control groups. If a low-fat diet reduces breast cancer risk, the effect is unlikely to be through changes in mammographic density at menopause.

Intervention with a low-fat, high-carbohydrate diet does not influence the timing of menopause.

BACKGROUND: Later age at menopause is associated with a greater risk of breast cancer. Dietary factors may at least partially influence breast cancer risk through an effect on the age at menopause. OBJECTIVE: We studied the effect of a low-fat, high-carbohydrate (LFHC) dietary intervention on the timing of menopause in women with greater risk of breast cancer. DESIGN: The study population included participants from an LFHC dietary intervention trial for the prevention of breast cancer in women with extensive mammographic density, a strong risk factor for breast cancer. Women who were premenopausal at baseline (n = 2611) were followed for an average of 7 y for menopause. Survival analysis was used to compare the time to menopause between the LFHC and control groups and to assess other factors associated with age at menopause. RESULTS: The LFHC intervention did not affect the time to natural menopause overall (P = 0.72 for log-rank test comparing study groups; n = 699 events). An observed interaction between study group and baseline body mass index (BMI; P = 0.01) indicated that the intervention group experienced earlier menopause than did the control group when BMI was low and that a higher BMI was associated with later menopause in the intervention group only. Greater parity, weight, and education were associated with later menopause, and greater age at first birth and baseline smoking were associated with earlier menopause. CONCLUSIONS: Overall, the LFHC dietary intervention did not influence the timing of menopause. Factors associated with age at menopause in this population were consistent with those reported in other populations.