Abstract
Background
In this study, we aim to uncover the relationship between estrogen levels and the genetic polymorphism of estrogen metabolism-related enzymes with breast cancer (BC) and establish a risk prediction model based on polygenic risk score.
Methods
Unrelated BC patients and healthy subjects were recruited for analysis of the estrogen levels and the single nucleotide polymorphisms (SNPs) of estrogen metabolism-related enzymes. The polygenic risk score (PRS) was used to explore the combined effect of multiple genes which was calculated using a Bayesian approach. The independent sample t test was used to evaluate the difference between PRS scores of BC and healthy subjects. Discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve (ROC).
Results
The estrogen homeostasis profile was disturbed in BC patients, with parent estrogens (E1, E2) and carcinogenic catechol estrogens (2/4-OHE1, 2-OHE2, 4-OHE2) significantly accumulated in the serum of BC patients. Then,we established PRS model to evaluate the role of multiple genes SNPs. The PRS model 1 (M1) was established from 6 GWAS-identified high risk genes SNPs. On the basis of M1, we added 7 estrogen metabolism enzyme genes SNPs to establish PRS model 2 (M2). The independent sample t test results show that there is no difference between BC and healthy subjects in M1 (P = 0.17), however, there is significant difference between BC and healthy subjects in M2 (P = 4.9*10− 5). The ROC curve results also show that the accuracy of M2 (AUC = 62.18%) in breast cancer risk identification was better than M1 (AUC = 54.56%).
Conclusion
Estrogens and the related metabolic enzymes gene polymorphisms are closely related to BC. The model constructed by adding estrogen metabolic enzyme genes SNPs has a good ability in breast cancer risk prediction, and the accuracy is greatly improved comparing PRS model only includes GWAS-identified genes SNPs.
The Discovery of Breast Cancer Risk Gene and Establishment of Prediction Model Based on Estrogen Metabolism Regulation
