Certain gene sets, early-life adiposity appear to increase breast cancer risk

Women with certain gene sets who reported early-life adiposity appeared to have an increased risk for breast cancer throughout life, according to study results published in Journal of the National Cancer Institute.

These gene sets appeared associated specifically with an increased risk for ER-positive and ER-negative breast cancers, researchers noted.

“Cumulative epidemiologic evidence has shown that early-life adiposity is strongly inversely associated with breast cancer risk throughout life, independent of adult obesity. However, the molecular mechanisms remain poorly understood,” Jun Wang, PhD, assistant professor of research preventive medicine at Keck School of Medicine of USC, and colleagues wrote.

Researchers sought to assess the association between early-life adiposity and the transcriptome of breast tumors (n = 835) and tumor-adjacent histologically normal tissue (n = 663) among women included in the Nurses’ Health Study and Nurses’ Health Study II. For the purpose of this study, researchers defined early-life adiposity as self-reported body size during the ages of 10 to 20 years.

The investigators conducted a multivariable linear regression analysis to identify differentially expressed genes in tumor and tumor-adjacent tissue and performed a molecular pathway analysis using hallmark gene sets (n = 50) to gain biological insights.

They stratified analyses by tumor ER protein expression status. Overall, 673 women (80.6%) had ER-positive breast cancer and 162 (19.4%) had ER-negative disease. Most women were white (95.4%) and had stage I or stage II breast cancer (> 90%).

The majority (81.9%) reported having a medium body shape during early life, whereas 10.9% of women reported having the leanest body shape and 7.2% reported a large body shape.

Even after adjusting for multiple comparisons, no genes appeared to be significantly differentially expressed according to body size during early life.

However, pathway analysis showed various significant up or down regulated gene sets (false discovery rate, < .05). The six most common genes identified included HMGA1, STMN1, MKI67, MCM3, KPNA2 and RAD21. Researchers found KPNA2 to be the only common gene within the proliferation-related gene sets.

Women who had higher early-life adiposity had decreased cellular proliferation pathways, including MYC target genes, in both ER-positive and ER-negative tumors.

Among those with ER-positive tumors, having a larger body size in early life was associated with upregulation in genes involved in tumor necrosis factor-alpha/NF-kappa-B signaling. For women with ER-negative tumors, larger body size correlated with downregulation in genes involved in interferon-alpha and interferon-gamma immune response and PI3K/ATK/mTOR signaling.

“The [interferon-gamma] response pathway was also downregulated in ER-tumor-adjacent tissue, though at borderline statistical significance,” Wang and colleagues wrote. “These findings provide new insights into the biological and pathological underpinnings of early-life adiposity and breast cancer association.”

The lack of validation of the identified gene sets in an independent data set, the fact that tumor tissue microarrays were created from whole tissue sections — causing potential confounding due to heterogeneity in tissue components across samples — and the definition of early life as a wide age range served as significant limitations of the study, according to the researchers.

“However, the reason for using this time of life is mainly because the inverse association of early-life adiposity with breast cancer risk appears to be strongest for the average body size during ages 10 and 20 years compared with that at one time point,” Wang and colleagues wrote. “Finally, the study was predominately white women, while the inverse association of early-life adiposity with breast cancer risk has been observed in minority women, thus, future studies in ethnically diverse populations are warranted.”

Considering the lack of prevention options for premenopausal breast cancer, funding should be provided immediately for more extensive studies of these pathways and how they can be targeted in breast cancer prevention, according to an editorial accompanying the study by Graham A. Colditz, MD, DrPH, and Adetunji T. Toriola, MD, PhD, both researchers in the department of surgery at Washington University School of Medicine in St. Louis.

“There are three key implications from this analysis. First, the use of hallmark gene sets by Wang and colleagues to identify biologically relevant pathways is a notable strength and an important benchmark for future studies to follow,” Colditz and Toriola wrote. “Second, the strong associations of early-life adiposity with immune response/inflammation and PI3K/AKT/mTOR signaling in ER-negative tumors underscores the need to design studies targeting these pathways to reduce the incidence of ER-negative tumors.

“Third, while findings in relation to early-life and adolescent adiposity are well-established in epidemiological literature, the study brings focus to the separate pathways of early adiposity from later adult weight gain, with the effect of early-life adiposity being more prominent on nonhormonal pathways compared with adult weight-gain acting mainly through hormonal pathways,” they wrote.

Greater understanding of these pathways can help identify preventive efforts, they added.

References:

Colditz GA and Toriola AT. J Natl Cancer Inst. 2020;doi:10.1093/jnci/djaa173.
Wang J, et al. J Natl Cancer Inst. 2020;doi:10.1093/jnci/djaa169.