Polymorphisms ofESR1, UGT1A1, HCN1, MAP3K1andCYP2B6are associated with the prognosis of hormone receptor-positive early breast cancer

// Sung-Hsin Kuo 1, 5, 6, 7 , Shi-Yi Yang 8 , San-Lin You 9, 10 , Huang-Chun Lien 2 , Ching-Hung Lin 1, 6 , Po-Han Lin 3 , Chiun-Sheng Huang 4 1 Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 2 Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 3 Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 4 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 5 Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan 6 Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan 7 National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan 8 Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan 9 School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan 10 Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan Correspondence to: Chiun-Sheng Huang, email: huangcs@ntu.edu.tw Keywords: genetic polymorphism, GWAS, breast cancer, prognostic factor, survival Received: August 01, 2016 Accepted: January 03, 2017 Published: February 02, 2017 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.