Genetic polymorphisms of 3′-untranslated region of SULT1A1 and their impact on tamoxifen metabolism and efficacy

Autor: Henk-Jan Guchelaar, Vincent O. Dezentjé, Jesse J. Swen, D J A R Moes, Hans Gelderblom, A B Sanchez-Spitman
Rok vydání: 2018
Předmět:
Zdroj: Breast Cancer Research and Treatment, 172(2), 401-411
Breast Cancer Research and Treatment
ISSN: 1573-7217
0167-6806
DOI: 10.1007/s10549-018-4923-7
Popis: Purpose Tamoxifen has a wide inter-variability. Recently, two SNPs in the 3′-untranslated region (UTR) of the SULT1A1 gene, rs6839 and rs1042157, have been associated with decreased SULT1A1 activity. The aim of this study is to investigate the role of the rs6839 and rs1042157 on tamoxifen metabolism and relapse-free survival (RFS) in women diagnosed with early-breast cancer receiving tamoxifen. Methods Samples from 667 patients collected in the CYPTAM study (NTR1509) were used for genotyping (CYP2D6, SULT1A1 rs6839 and rs1042157) and measurements of tamoxifen and metabolites. Patients were categorized in three groups depending on the decreased SULT1A1 activity due to rs6839 and rs1042157: low activity group (rs6839 (GG) and rs1042157 (TT)); high activity group (rs6839 (AA) and rs1042157 (CC)); and medium activity group (all the other combinations of rs6839 and rs1042157). Associations between SULT1A1 phenotypes and clinical outcome (RFS) were explored. Results In the low SULT1A1 activity group, higher endoxifen and 4-hydroxy-tamoxifen concentrations were found, compared to the medium and high activity group (endoxifen: 31.23 vs. 30.51 vs. 27.00, p value: 0.016; 4-hydroxy-tamoxifen: 5.55 vs. 5.27 vs. 4.94, p value:0.05). In terms of relapse, the low activity group had a borderline better outcome compared to the medium and high SULT1A1 activity group (adjusted Hazard ratio: 0.297; 95% CI 0.088–1.000; p value: 0.05). Conclusion Our results suggested that rs6839 and rs1042157 SNPs have a minor effect on the concentrations and metabolic ratios of tamoxifen and its metabolites, and RFS in women receiving adjuvant tamoxifen. Electronic supplementary material The online version of this article (10.1007/s10549-018-4923-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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