Mammographic density mediates the protective effect of early-life body size on breast cancer risk

Marina Vabistsevits (), George Davey Smith, Tom G. Richardson, Rebecca C. Richmond, Weiva Sieh, Joseph H. Rothstein, Laurel A. Habel, Stacey E. Alexeeff, Bethan Lloyd-Lewis and Eleanor Sanderson
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Marina Vabistsevits: MRC Integrative Epidemiology Unit
George Davey Smith: MRC Integrative Epidemiology Unit
Tom G. Richardson: MRC Integrative Epidemiology Unit
Rebecca C. Richmond: MRC Integrative Epidemiology Unit
Weiva Sieh: Department of Population Health Science and Policy
Joseph H. Rothstein: Department of Population Health Science and Policy
Laurel A. Habel: Division of Research
Stacey E. Alexeeff: Division of Research
Bethan Lloyd-Lewis: School of Cellular and Molecular Medicine
Eleanor Sanderson: MRC Integrative Epidemiology Unit

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%–79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

Date: 2024
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DOI: 10.1038/s41467-024-48105-7

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