细胞色素P450 2D6与同源盒13/白细胞介素-17B受体：联合遗传性和肿瘤基因标志物预测他莫昔芬耐药性
Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor: combining inherited and tumor gene markers for prediction of tamoxifen resistance.
作者信息
Goetz Matthew P, Suman Vera J, Couch Fergus J, Ames Matthew M, Rae James M, Erlander Mark G, Ma Xiao-Jun, Sgroi Dennis C, Reynolds Carol A, Lingle Wilma L, Weinshilboum Richard M, Flockhart David A, Desta Zeruesenay, Perez Edith A, Ingle James N
机构信息
Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
出版信息
Clin Cancer Res. 2008 Sep 15;14(18):5864-8. doi: 10.1158/1078-0432.CCR-08-0619.
PURPOSE
Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer.
EXPERIMENTAL DESIGN
Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central Cancer Treatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6*4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling.
RESULTS
CYP2D6 metabolism and HOXB13/IL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13/IL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% CI, 1.17-8.52; P = 0.024).
CONCLUSIONS
An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.
目的
细胞色素P450 2D6（CYP2D6）的基因变异以及同源盒13（HOXB13）与白细胞介素-17B受体（IL17BR）的基因表达比率与他莫昔芬耐药相关。我们试图确定遗传性（CYP2D6）和体细胞性（HOXB13/IL17BR）基因变异在接受他莫昔芬治疗的乳腺癌中的联合效应。
实验设计
对被随机分配接受5年他莫昔芬治疗的淋巴结阴性乳腺癌女性进行回顾性分析（北中部癌症治疗组89 - 30 - 52）。CYP2D6代谢（广泛或降低）基于CYP2D6*4基因型以及是否存在CYP2D6抑制剂。使用HOXB13和IL17BR的逆转录 - PCR谱以及根据无病生存期（DFS）将患者分为高风险和低风险类别的切点。创建了一个代表CYP2D6代谢（广泛或降低）与HOXB13/IL17BR（低或高）组合的四类别的风险因素（CYP2D6:HOXB13/IL17BR）。使用对数秩检验和比例风险模型评估CYP2D6:HOXB13/IL17BR与DFS和总生存期（OS）之间的关联。
结果
160例患者中有110例（69%）可获得CYP2D6代谢和HOXB13/IL17BR基因比率。联合的CYP2D6:HOXB13/IL17BR风险因素与DFS（对数秩P = 0.004）和OS（P = 0.009）显著相关。相对于CYP2D6代谢广泛且HOXB13/IL17BR低的女性，代谢降低或HOXB13/IL17BR比率高的女性OS显著更差（调整后的风险比，2.41；95%置信区间，1.08 - 5.37；P = 0.031），而代谢降低且HOXB13/IL17BR比率高的女性生存期最短（调整后的风险比，3.15；95% CI，1.17 - 8.52；P = 0.024）。
结论
由遗传性（CYP2D6）和肿瘤性（HOXB13/IL17BR）基因变异组成的指标可识别对他莫昔芬具有不同程度耐药性的患者。
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