Having a larger body size just before entering puberty critically influences a woman’s risk of breast cancer during her most fertile years, research suggests.
The genome-wide association study, in Science Advances, highlights the importance of early life stages as important windows of susceptibility for disease.
The findings revealed that that prepubertal adiposity, occurring just before puberty and often considered between the ages of nine and 12 years, had an important impact in lowering breast cancer risk among women aged less than 40 years.
It mostly accounted for the benefits of body mass index (BMI) in decreasing breast cancer risk, and suggested protection may arise from greater adiposity in both childhood and early adulthood.
“These results have important implications for breast cancer prevention, underscoring earlier life stages as critical periods for potential interventions,” maintained Grace Power, PhD, from the University of Bristol, and colleagues.
Power and team evaluated data on 56,628 child-free women collected between the age of first menstruation and either first childbirth or the age of 40 years, whichever came first.
Specifically, they used longitudinal data from genome-wide association studies to examine how BMI mediated the risk of breast cancer through its influence on the genome.
Genetic architectures were examined at distinct life stages: menarche to less than 20 years; 20 to below 30 years; and from 30 to below 40 years.
The researchers conducted Mendelian randomization (MR) analyses, which estimate causal effects by reducing susceptibility to confounding factors such as undiagnosed disease or disease processes.
They observed genetic effects on BMI across different life stages for nine of 45 variants, with several showing clear changes in the direction of effect across life stages.
Univariable Mendelian analyses revealed that higher BMI consistently reduced the risk of overall breast cancer, as well as most of the seven subtypes studied.
However, this was mostly—albeit not entirely—accounted for by childhood body size, which was used as a proxy for BMI in multivariable MR (MVMR).
Power and colleagues acknowledge that two distinct early-life pathways influence breast cancer risk.
“While a larger body size in early life appears protective, it may also accelerate age at menarche, which is itself a risk factor for breast cancer, suggesting that these pathways are not only independent but may interact in complex ways,” they elaborated.
The team added: “Although MVMR provides a valuable sensitivity analysis, it may not fully disentangle the independent contributions of adiposity and pubertal timing, particularly where shared pathways act differently across breast cancer subtypes.
“Furthermore, increased prepubertal body size has been shown to decrease breast density, while age at menarche has been linked to higher breast density, which is another important risk factor for breast cancer.
“This distinction between pathways highlights the need to examine potential mediating factors, which may help clarify the mechanisms at play.”
