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

Sung-Hsin Kuo,Shi-Yi Yang,Huang-Chun Lien,San-Lin You,Po-Han Lin,Chiun-Sheng Huang,Ching-Hung Lin

doi:10.18632/oncotarget.14995

Sung-Hsin Kuo, Shi-Yi Yang + Show 5 more

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https://doi.org/10.18632/oncotarget.14995

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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.

Highlights

Postoperative adjuvant systemic therapy is considered to be an integral component of the management of primary breast cancer [1, 2]
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
We demonstrated that genetic variants of the host, such as SNPs of MAP3K1, CYP2B6, UGT1A1, HCN1, ABCB1, and ALDH3A1, may worse the prognosis of HR-positive breast cancer patients, predominantly for premenopausal women

Summary

Introduction

Postoperative adjuvant systemic therapy is considered to be an integral component of the management of primary breast cancer [1, 2]. Our and others’ studies have previously demonstrated that patients with different genotypes of single nucleotide polymorphisms (SNPs) of estrogen and tamoxifen metabolizing genes, such as CYP19, COMT, CPY2D6, and SULT1A1, may carry different responses to anti-estrogen treatment and have different outcomes [7,8,9,10,11] In addition to these candidate genes, SNPs identified from genome-wide association studies (GWAS) have been found to be associated with breast cancer risk [12,13,14,15,16] and survival [17, 18]. We hypothesized that host factors, as shown by SNPs identified from GWAS and SNPs of genes involved in the metabolism of estrogen, tamoxifen, and chemotherapeutic agents (Figure 1), may influence the effect of adjuvant treatment, and the survival of breast cancer patients

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