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Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.
The Pharmacogenomics Journal ( IF 2.9 ) Pub Date : 2019-04-10 , DOI: 10.1038/s41397-019-0087-z
Harriet Johansson 1 , Valentina Aristarco 1 , Sara Gandini 2 , Jennifer Gjerde 3, 4 , Debora Macis 1 , Aliana Guerrieri-Gonzaga 1 , Davide Serrano 1 , Matteo Lazzeroni 1 , Agnita Rajasekaran 5 , Clark V Williard 5 , Gunnar Mellgren 3, 4 , Andrea DeCensi 6, 7 , Bernardo Bonanni 1
Affiliation  

Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with "any event" was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20-1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P < 0.004). After a median follow-up of 7 years, women carrying the "low estrogen" alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17-0.93; P = 0.03). Our analysis points to an impact of UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592.

中文翻译:

CYP19A1 和 UGT2B17 基因变异在内分泌反应性绝经后乳腺癌随机试验中的预后影响。

参与雌激素合成的基因多态性与乳腺癌风险、预后和治疗反应有关。我们调查了跨越整个 UGT2B17 基因 (UGT2B17*2) 的缺失以及芳香酶 CYP19A1 和雌激素受体 α (ESR1) 的遗传变异对 125 名 ER 阳性乳腺癌绝经后妇女的预后影响,这些女性参加了一项随机手术前试验. UGT2B17 * 2 通过拷贝数变异分析估计,CYP19A1 rs10046/rs4646 和 ESR1 rs2077647/rs2234693/rs9340799 通过 TaqMan 等位基因鉴别分析估计。血清依西美坦/17-羟基依西美坦由 MS 测定,雌酮 (E1)/雌二醇 (E2)/ GC-MS/MS 测定。通过针对混杂因素调整的 Cox 比例风险模型评估遗传多态性与“任何事件”的关联。与纯合子 UGT2B17 wt 相比,UGT2B17*2 与更高水平的 17-羟基依西美坦 (P = 0.04) 和更好的预后 (HR = 0.45; 95% CI: 0.20-1.01; P = 0.05) 相关。CYP19A1 rs10046 A 和 rs4646 C 等位基因与较高的雌激素水平相关:rs10046 AA 与 AG/GG 基因型的中位 E1 为 35.9 与 27.4 pg/mL(P = 0.05),E2 为 7.57 与 3.9 pg/mL( P < 0.004)。中位随访 7 年后,携带“低雌激素”等位基因 rs10046 G 和 rs4646 A 的女性与纯合子 wt 相比,两种多态性的预后更好(HR = 0.40;95% CI:0.17-0.93;P = 0.03 )。我们的分析指出了 UGT2B17 和 CYP19A1 在绝经后内分泌反应性乳腺癌中的影响。UGT2B17*2 和 CYP19A1 低雌激素变异体的携带者可能有更好的预后,支持研究这些多态性在优化内分泌治疗中的作用。试用注册:http://www.isrctn.com/ISRCTN86894592。
更新日期:2019-11-18
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