Association of Estrogen-Related Polygenetic Risk Scores with Breast Cancer and Interactions with Alcohol Intake, Early Menarche, and Nulligravida.

Suna Kang,Sang Shin Song,Sunmin Park

doi:10.31557/apjcp.2022.23.1.13

Suna Kang, Sang Shin Song + Show 1 more

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https://doi.org/10.31557/apjcp.2022.23.1.13

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Abstract

Backgrounds:Early menstruation, late menopause, no pregnancy, and genetic factors are known risk factors of the disease, but their effects may differ in Asian and Caucasian women. The purpose of this study was to identify genetic variants of genes related to estrogen signaling in a large city hospital-based cohort and to determine their interactions with lifestyles. Methods:This is a case-control study. Three hundred ninety participants diagnosed with breast cancer were compared with 36,290 controls(no cancer)to explore the genetic variants to influence breast cancer risk. Based on GWAS results, the selected genetic variants were subjected to their interactions by generalized multifactor dimensionality reduction (GMDR) analysis. Results:Early menstruation(OR=1.55), early menopause (OR=1.70), and no experience of pregnancy(OR=2.86) had a positive association with breast cancer risk(P<0.05). The selected polygenetic risk score(PRS) models included four SNPs and seven SNPs: The four-SNP PRS model included CDH13_rs12600325, SMYD3_rs3753686, FGF12_rs2134635, and ESRRB_rs10873289, and in the seven-SNP PRS model, ESR1_ rs2046210, estrogen-related receptor gamma(ESRRG)_rs17043393, and EGFR_ rs6958497 were added into the four-SNP PRS model. Early menstruation, early menopause, and no pregnancy experience interacted with four-SNP PRS. For the participants who had early menstruation and early menopause, high-PRS had an association with a much higher breast cancer risk than the low-PRS in the four-SNP model. However, metabolic parameters, nutrient intakes, and different dietary patterns did not interact with PRS for breast cancer risk. However, alcohol intake interacted with PRS for breast cancer risk (OR=2.33 and 8.07 for mild and moderate alcohol consumption, respectively; P=0.0004). Conclusion:Consideration of age at menarche and menopause, pregnancy experience, and alcohol intake may be required to reduce breast cancer risk in women with a high-PRS of genes related to the estrogen signaling pathway.

Highlights

Breast cancer is the most common cancer and has a lifetime prevalence of about 12% in women in the USA (Harbeck and Gnant, 2017)
We explored the genetic variants of genes related to estrogen receptor signaling and their influence on breast cancer
generalized multifactor dimensionality reduction (GMDR) analysis of 493 genetic variants detected in the breast-cancer and the control groups identified ten gene variants related to estrogen signaling

Summary

Introduction

Breast cancer is the most common cancer and has a lifetime prevalence of about 12% in women in the USA (Harbeck and Gnant, 2017). Endogenous and exogenous factors influence the etiology of breast cancer. Breast epithelial cells grow and function under female hormone control (Harbeck et al, 2019). Estrogen is associated with the mitotic activity of breast epithelial cells, and excessive estrogen exposure increases their excessive proliferation and increased the mutation rates to increase breast cancer risk (Harbeck et al, 2019). The risk factors of breast cancer known to interact with estrogen exposure are age, age at menarche and menopause, pregnancy experience, breastfeeding period, hormone replacement therapy, and obesity (Harkness et al, 2020). The association between estrogen exposure and breast cancer development remains unclear

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