J Breast Cancer.  2017 Mar;20(1):27-34. 10.4048/jbc.2017.20.1.27.

Genetic Predisposition of Polymorphisms in HMGB1-Related Genes to Breast Cancer Prognosis in Korean Women

• Lee J
• Choi J
• Chung S
• Park J
• Kim JE
• Sung H
• Han W
• Lee JW
• Park SK
• Kim MK
• Ahn SH
• Noh DY
• Yoo KY
• Kang D
• Choi JY

• KMID: 2379396
• DOI: http://doi.org/10.4048/jbc.2017.20.1.27

Abstract

PURPOSE
The high mobility group box 1 (HMGB1) protein has roles in apoptosis and immune responses by acting as a ligand for receptor for advanced glycation end products (RAGE), Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 1. In particular, HMGB1/RAGE is involved in tumor metastasis by inducing matrix metalloproteinase 2 (MMP2) and MMP9 expression. We investigated the associations between genetic variations in HMGB1-related genes and disease-free survival (DFS) and overall survival (OS) in Korean female breast cancer patients.
METHODS
A total of 2,027 patients in the Seoul Breast Cancer Study were included in the analysis. One hundred sixteen single nucleotide polymorphisms (SNPs) were extracted from eight genes. A multivariate Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) of each SNP. The effects of the SNPs on breast cancer prognosis were assessed at cumulative levels with polygenic risk scores.
RESULTS
The SNPs significantly associated with DFS were rs243867 (hazard ratio, 1.26; 95% CI, 1.05-1.50) and rs243842 (hazard ratio, 1.24; 95% CI, 1.03-1.50); both SNPs were in MMP2. The SNPs significantly associated with OS were rs243842 in MMP2 (hazard ratio, 1.33; 95% CI 1.03-1.71), rs4145277 in HMGB1 (hazard ratio, 1.29; 95% CI, 1.00-1.66), rs7656411 in TLR2 (hazard ratio, 0.76; 95% CI, 0.60-0.98), and rs7045953 in TLR4 (hazard ratio, 0.50; 95% CI, 0.29-0.84). The polygenic risk score results for the DFS and OS patients showed third tertile hazard ratios of 1.72 (95% CI, 1.27-2.34) and 2.75 (95% CI, 1.79-4.23), respectively, over their first tertile references.
CONCLUSION
The results of the present study indicate that genetic polymorphisms in HMGB1-related genes are related to breast cancer prognosis in Korean women.

Keyword

Breast neoplasms; HMGB1 protein; Matrix metalloproteinase 2; Survival

MeSH Terms

Advanced Glycosylation End Product-Specific Receptor
Apoptosis
Breast Neoplasms*
Breast*
Disease-Free Survival
Female
Genetic Predisposition to Disease*
Genetic Variation
HMGB1 Protein
Humans
Matrix Metalloproteinase 2
Myeloid Cells
Neoplasm Metastasis
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Prognosis*
Proportional Hazards Models
Seoul
Toll-Like Receptors
Advanced Glycosylation End Product-Specific Receptor
HMGB1 Protein
Matrix Metalloproteinase 2
Toll-Like Receptors

Figure

• 

  Figure 1 Kaplan-Meier survival curves of each tertile group based on the polygenic risk scores (PRS) of (A) 2,009 patients with two single nucleotide polymorphisms (SNPs) associated with disease-free survival (DFS) and (B) 2,004 patients with four SNPs associated with overall survival (OS).

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