Corresponding Author: Heinz-Josef Lenz, Sharon A. Carpenter Laboratory, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 1441 Eastlake Avenue, Los Angeles, CA 90033.
Mol Cancer Ther. 2013 Oct;12(10):2261-72. doi: 10.1158/1535-7163.MCT-12-1134. Epub 2013 Aug 5.
Lemur tyrosine kinase-3 (LMTK3) was recently identified as an estrogen receptor (ER)-α modulator related to endocrine therapy resistance, and its polymorphisms rs9989661 (T>C) T/T genotype and rs8108419 (G>A) G/G or A/G genotype predicted improved outcomes in breast cancer. Because different predominant ER distributions link to breast and gastric cancer and little is known of the prognostic role of LMTK3 in gastric cancer, this study was carried out to clarify the prognostic role of these polymorphisms in gastric cancer. One-hundred and sixty-nine Japanese and 137 U.S. patients with localized gastric adenocarcinoma were enrolled. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA sequencing. Overall, these polymorphisms were not associated with survival in both cohorts. When gender was considered, in multivariate analysis, harboring rs9989661 T/T genotype was associated with disease-free survival [HR, 4.37; 95% confidence interval (CI), 2.08-9.18; P < 0.0001] and overall survival (OS; HR, 3.69; 95% CI, 1.65-8.24; P = 0.0014) in the Japanese males and time to recurrence (HR, 7.29; 95% CI, 1.07-49.80; P = 0.043) in the U.S. females. Meanwhile, harboring rs8108419 G/G genotype was associated with OS in the Japanese females (HR, 3.04; 95% CI, 1.08-8.56; P = 0.035) and the U.S. males (HR, 3.39; 95% CI, 1.31-8.80; P = 0.012). The prognostic role of these polymorphisms may be negative in gastric cancer. These findings suggest that the estrogen pathway may play a prognostic role in patients with gastric cancer but this may be dependent on the regional differences both in physiology and genetic alterations of gastric cancer.
Lemur 酪氨酸激酶-3（LMTK3）最近被确定为与内分泌治疗耐药相关的雌激素受体（ER）-α调节剂，其多态性 rs9989661（T>C）T/T 基因型和 rs8108419（G>A）G/G 或 A/G 基因型预测乳腺癌的预后改善。由于不同的主要 ER 分布与乳腺癌和胃癌相关，并且对于 LMTK3 在胃癌中的预后作用知之甚少，因此进行了这项研究以阐明这些多态性在胃癌中的预后作用。纳入了 169 名日本和 137 名美国局限性胃腺癌患者。从血液或组织中提取基因组 DNA，并通过基于 PCR 的直接 DNA 测序对所有样本进行分析。总体而言，这些多态性与两个队列的生存均无关。当考虑到性别时，多变量分析表明，携带 rs9989661 T/T 基因型与日本男性的无病生存[HR，4.37；95%置信区间（CI），2.08-9.18；P <0.0001]和总生存（OS；HR，3.69；95%CI，1.65-8.24；P = 0.0014）以及美国女性的复发时间（HR，7.29；95%CI，1.07-49.80；P = 0.043）相关。同时，携带 rs8108419 G/G 基因型与日本女性的 OS 相关（HR，3.04；95%CI，1.08-8.56；P = 0.035）和美国男性的 OS 相关（HR，3.39；95%CI，1.31-8.80；P = 0.012）。这些多态性的预后作用在胃癌中可能是负面的。这些发现表明，雌激素通路可能在胃癌患者中发挥预后作用，但这可能取决于生理和胃癌遗传改变的区域差异。
