Polymorphisms of ESR1, UGT1A1, HCN1, MAP3K1 and CYP2B6 are associated with the prognosis of hormone receptor-positive early breast cancer

Abstract

In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10.6 years, 363 patients were alive, and 51 (12.3%) had died. Multiple-adjusted hazard ratios (aHRs) and the corresponding 95% confidence intervals for distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS) in association with the genotypes of 34 SNPs from the above-mentioned 16 genes were evaluated, using the stepwise selection Cox model. We found that the SNP, ESR1-codon325 rs1801132 (G/G+G/C), was associated with a longer DDFS, whereas UGT1A1 rs4148323 (A/A+A/G), and HCN1 rs981782 (A/A+A/C) were significantly associated with poorer DDFS. MAP3K1 rs889312 (C/C) and CYP2B6 rs3211371 (T/C) were significantly associated with poor DFS, DDFS and OS. Among premenopausal women, MAP3K1 rs889312 (C/C), CYP2B6 rs3211371 (T/C), CYP2B6 rs4802101 (T/T), ABCB1 rs2032582 (C/C), and ALDH3A1 rs2231142 (G/G) were significantly associated with poor DDFS, DFS, or OS. Our results provide additional evidence that genetic polymorphisms observed in SNPs are associated with the prognoses of patients with HR-positive breast cancers; this may indicate different treatment strategies for these patients.

Keywords: GWAS; breast cancer; genetic polymorphism; prognostic factor; survival.

Figure 1. Schema illustrating single nucleotide polymorphisms that involved in the metabolism of estrogen, tamoxifen, and chemotherapeutic agents, and cell proliferation of hormone receptor-positive breast cancer

A. Candidate genes involved in the metabolism of estrogen, such as CYP19, COMT, ESR1, UGT1A1, and CYP3A5 B. Candidate genes involved in the metabolism of tamoxifen, such as CYP2C9, CYP2C19, CYP3A5, and CYP2D6 C. Candidate genes involved in the metabolism of chemotherapeutic agents, such as ABCB1, ALDH3A1, and CYP2B6 D. Genome-wide association studies-derived genes involved in the cell proliferation of breast cancer cells, such as MAP3K1 and FGFR2.

Figure 2. The association between single nucleotide polymorphisms of MAP3K1 rs889312 and prognosis of hormone receptor-positive early-stage breast cancer

A. Disease-free survival (DFS)) B. Distant disease-free survival (DDFS) C. overall survival (OS).