SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER plus breast cancer: genome-wide association studies of the estrone pathway
SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER plus breast cancer: genome-wide association studies of the estrone pathway
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DOI：
10.1007/s10549-017-4243-3
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发表时间：
2017-07-01
影响因子：
3.8
通讯作者：
Weinshilboum, Richard M.
中科院分区：
文献类型：
--
作者：
Dudenkov, Tanda M.;Ingle, James N.;Weinshilboum, Richard M.
雌酮（E1）是绝经后妇女体内主要的循环雌激素，可促进雌激素受体阳性（ER+）乳腺肿瘤的生长和增殖。两个主要反应有助于E1血浆浓度，芳香酶（CYP 19 A1）催化雄烯二酮合成E1和类固醇硫酸酯酶（STS）催化雌酮结合物（E1 C）水解。E1 Cs已与乳腺癌的风险，并可能有助于肿瘤的进展，因为STS是在乳腺癌中表达，其活动超过了aromatase.Methods我们进行了全基因组关联研究（GWAS），以确定单核苷酸多态性与E1 Cs，E1和雄烯二酮的血浆浓度的变化在774绝经后妇女切除早期ER+乳腺癌。芳香化酶抑制剂therapeutic.Results多个SNPs在SLCO 1B 1，一个基因编码的肝内流转运蛋白，显示全基因组的显着关联与E1 C血浆浓度和E1 C/E1比值。E1 C浓度的最高SNP rs 4149056（p = 3.74E-11）是导致转运蛋白活性降低的错义变体。变异等位基因纯合子患者的平均E1 C血浆浓度显著高于其他患者。此外，其他三个SLCO 1B 1 SNP，而不是在LD与rs 4149056，都与E1 C浓度和E1 C/E1比值和SLCO 1B 3的顺式eQTL。GWAS信号的提示意义也观察到E1，雄烯二酮，和E1/androstenedione ratio.Conclusion这些结果表明E1 C血浆浓度的遗传变异的机制，以及可能的SNP生物标志物，以确定ER+乳腺癌患者的STS抑制剂可能具有临床价值。
Background Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase.Methods We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy.Results Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E-11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio.Conclusion These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.