Mammographic Density Is Highly Heritable, Possibly Explaining the Familial Aggregation of Breast Cancer

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Using a fully automated method to ascertain volumetric mammographic density, a study conducted by the Karolinska Mammography (KARMA) project for risk prediction of breast cancer in Sweden confirmed the high heritability of mammographic density, although estimates were weaker for absolute than for percent dense volume of breast tissue. “These data support the notion that mammographic density is a risk factor under strong genetic influence that may partially explain the familial aggregation of breast cancer,” Judith S. Brand, PhD, of the Karolinska Institutet in Stockholm, and colleagues wrote in the Journal of the National Cancer Institute.

“Mammographic density, which reflects the amount of fibroglandular or radiodense tissue in the breast, is a strong determinant of breast cancer risk,” the authors explained. “Although the exact mechanisms underlying the association between mammographic density and breast cancer are not completely understood, both traits share several risk factors, including nulliparity, late age at first birth, and hormone replacement therapy. Apart from an overlap in environmental risk factors, there is also evidence of a shared genetic basis.”

Previous studies to investigate the genetic basis of mammographic density have relied on either qualitative or semiautomated measures. “The main disadvantage of these measures is that they are reader-dependent and do not acknowledge the three-dimensional structure of the breast,” the researchers wrote. “Fully automated measures of volumetric mammographic density may provide more accurate measures, as they incorporate information on breast thickness.”

Study Details and Clinical Implications

Heritability of volumetric mammographic density was estimated with a variance component model in a sample of 955 pairs of full or half sisters. For the breast cancer single nucleotide polymorphism analysis, researchers chose a separate independent sample of 4,025 unrelated women who were genotyped. Associations with 82 established breast cancer loci were assessed using linear models, adjusting for age, body mass index, and menopausal status. “Single nucleotide polymorphism analyses were performed in cancer-free women, reducing the likelihood of artificial associations because of confounding by breast cancer,” the researchers noted. Both study populations had a mean age of 54 years at study entry and a mean body mass index of 25 kg/m2.

“After multivariable adjustment, heritability estimates (standard error) for percent dense volume, absolute dense volume, and absolute nondense volume were 0.63 (0.06) and 0.43 (0.06) and 0.61 (0.06), respectively (all P < .001),” the authors reported. Percent and absolute dense volumes were associated with two single nucleotide polymorphisms, associations with the absolute dense volume observed in two others, and absolute nondense volume in two additional single nucleotide polymorphisms.

“The breast cancer single nucleotide polymorphisms that have been identified to date explain only little of the variation in mammographic density, but the observed associations with individual single nucleotide polymorphisms are relevant, as they provide more insight into the biological mechanisms leading to breast cancer in women with highly dense breasts,” the authors stated. “In addition, the observed breast cancer single nucleotide polymorphism associations with the absolute nondense volume indicate that the shared genetic component with breast cancer is not restricted to dense tissues only.” ■

Brand JS, et al: J Natl Cancer Inst 106(12):dju334, 2014.