Udler Miriam S, Azzato Elizabeth M, Healey Catherine S, Ahmed Shahana, Pooley Karen A, Greenberg David, Shah Mitul, Teschendorff Andrew E, Caldas Carlos, Dunning Alison M, Ostrander Elaine A, Caporaso Neil E, Easton Douglas, Pharoah Paul D
Strangeways Research Laboratory, Departments of Public Health and Primary Care and Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom.
Int J Cancer. 2009 Dec 1;125(11):2687-96. doi: 10.1002/ijc.24678.
Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population-based case-control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69-0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted.
尽管初步证据表明,参与类固醇激素代谢的基因中的种系变异可能会改变乳腺癌的预后,但这尚未得到系统评估。我们在一项基于人群的病例对照研究SEARCH中,研究了参与类固醇激素代谢和信号通路的6个基因(COMT、CYP19A1、ESR1、PGR、SULT1E1、STS)中的种系多态性与乳腺癌女性患者生存率之间的关联。对多达4470名女性的血样进行基因分型,检测CYP19A1中4个可能的功能性单核苷酸多态性(SNP)以及标记其余基因常见变异的106个SNP。使用Cox回归分析测试每种多态性的基因型与乳腺癌诊断后生存率的关联。在共显性模型下,观察到COMT多态性(rs4818,p = 0.016)存在显著关联证据。该SNP似乎更符合显性模型(风险比=0.80,95%置信区间:0.69 - 0.95,p = 0.009);然而,在对多重假设检验进行排列分析调整后,结果仅具有边缘显著性(p = 0.047)。为了进一步评估这一发现,使用来自8个公开可用数据集的体细胞表达微阵列数据来测试生存率与肿瘤COMT基因表达之间的关联;未观察到具有统计学意义的关联。COMT中的一个相关SNP,rs4860,最近在显性模型中与中国女性的乳腺癌预后相关。这些结果表明,COMT rs4818或其标记的一个变体与乳腺癌预后相关。有必要对COMT及其与乳腺癌预后的假定关联进行进一步研究。