Genetic architecture of mammographic density as a risk factor for breast cancer: a systematic review

Shamshiri, Asma Khorshid; Alidoust, Maryam; Nokandei, Mahboubeh Hemmati; Pasdar, Alireza; Afzaljavan, Fahimeh

doi:10.1007/s12094-022-03071-8

Cited by 6 publications

(1 citation statement)

References 145 publications

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“…Despite using one of the largest MD GWAS cohorts to date (N=24,192) [32], the number of instruments was still relatively small (albeit higher than in earlier studies, such as [48], [59]). A summary table of all published MD GWAS studies is provided in a recent review [60]. A similarly sized MD GWAS conducted on data from the BCAC cohort (N=24,579-27,900) [61] has recently been released, but due to the unavailability of effect sizes, it is not possible to validate our findings using this resource.…”

Section: Discussionmentioning

confidence: 99%

The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study

Vabistsevits,

Smith,

Richardson

et al. 2023

Preprint

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Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR).We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD.Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% - 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA.In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.

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