Functional Genetic Polymorphisms in the Aromatase GeneCYP19Vary the Response of Breast Cancer Patients to Neoadjuvant Therapy with Aromatase Inhibitors

芳香化酶 乳腺癌 单核苷酸多态性 芳香化酶抑制剂 内科学 基因型 癌症 生物 阿那曲唑 肿瘤科 医学 内分泌学 癌症研究 基因 遗传学
作者
Liewei Wang,Katarzyna A. Ellsworth,Irene Moon,Linda L. Pelleymounter,Bruce W. Eckloff,Yvette N. Martin,Brooke L. Fridley,Gregory D. Jenkins,Anthony Batzler,Vera J. Suman,Saranya Ravi,J. Michael Dixon,William R. Miller,Eric D. Wieben,Aman U. Buzdar,Richard M. Weinshilboum,James N. Ingle
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:70 (1): 319-328 被引量:106
标识
DOI:10.1158/0008-5472.can-09-3224
摘要

Abstract Aromatase (CYP19) is a critical enzyme in estrogen biosynthesis and aromatase inhibitors (AI) are employed widely for endocrine therapy in postmenopausal women with breast cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in the CYP19 gene may alter the effectiveness of AI therapy in the neoadjuvant setting. Genomic DNA was obtained for sequencing from 52 women pre-AI and post-AI treatment in this setting. Additionally, genomic DNA obtained from 82 samples of breast cancer and 19 samples of normal breast tissue was subjected to resequencing. No differences in CYP19 sequence were observed between tumor and germ-line DNA in the same patient. A total of 48 SNPs were identified including 4 novel SNPs when compared with previous resequencing data. For genotype-phenotype association studies, we determined the levels of aromatase activity, estrone, estradiol, and tumor size in patients pre-AI and post-AI treatment. We defined two tightly linked SNPs (rs6493497 and rs7176005 in the 5'-flanking region of CYP19 exon 1.1) that were significantly associated with a greater change in aromatase activity after AI treatment. In a follow-up study of 200 women with early-stage breast cancer who were treated with adjuvant anastrozole, these same two SNPs were also associated with higher plasma estradiol levels in patients pre-AI and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed likely functional effects of these two SNPs on transcription of CYP19. Our findings indicate that two common genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to aromatase inhibitors. Cancer Res; 70(1); 319–28
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