Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Ann Surg Oncol. 2012 May;19(5):1560-7. doi: 10.1245/s10434-011-2157-6. Epub 2011 Dec 1.
DOK2 is known as the substrate of chmeric p210bcr/abl oncoprotein characterizing chronic myelogenous leukemia with Philadelphia chromosome. Reduced DOK2 expression was recently reported in lung adenocarcinoma, suggesting that this protein acts as a tumor suppressor in solid tumors. The purpose of this study was to determine the significance of DOK2 in gastric cancer.
The study subjects were 118 patients who underwent curative surgery for gastric cancer, as well as 7 gastric cancer cell lines. The tissues and cell lines were analyzed for DOK2 gene and protein expressions by histopathology and immunohistochemistry, and also using a microsatellite marker for loss of heterozygosity. Correlation of survival with clinicopathological parameters was investigated by univariate and multivariate analyses.
DOK2 expression was confirmed in the normal gastric mucosa. Considerable differences in the gene expression were noted among the gastric cell lines. Positive DOK2 expression was noted in the noncancerous regions of all pathological specimens, whereas 59 (50.0%) specimens of 118 patients were negatively stained in the tumor. Loss of heterozygosity was observed in 54.5% of DOK2(-) cases. DOK2(-) patients were more likely to develop recurrence than DOK2(+) and showed poorer 5-year overall survival (59.1%) than DOK2(+) (76.4%, P = .0403). Multivariate analysis identified pT (hazard ratio [HR] = 2.748, 95% confidence interval [95% CI] = 1.061-8.927, P = .0361), pN (HR = 2.486, 95% CI = 1.264-4.932, P = .0086), and DOK2(-) (HR = 2.343, 95% CI = 1.211-4.727, P = .0112) as significant and independent determinants of poor survival.
Our data suggest the potential usefulness of DOK2 as a marker of poor prognosis in patients with gastric cancer after curative resection.
DOK2 是费城染色体特征性慢性髓系白血病嵌合 p210bcr/abl 癌蛋白的底物。最近有报道称，DOK2 在肺腺癌中表达降低，提示该蛋白在实体瘤中起肿瘤抑制作用。本研究旨在确定 DOK2 在胃癌中的意义。
本研究对象为 118 例接受胃癌根治性手术的患者，以及 7 株胃癌细胞系。通过组织病理学和免疫组织化学分析以及微卫星标记物检测杂合性缺失，对组织和细胞系中的 DOK2 基因和蛋白表达进行分析。通过单因素和多因素分析研究生存与临床病理参数的相关性。
在正常胃黏膜中证实了 DOK2 的表达。胃癌细胞系的基因表达存在明显差异。所有病理标本的非癌区域均有阳性 DOK2 表达，而 118 例患者中有 59 例（50.0%）肿瘤呈阴性染色。DOK2(-)病例中观察到杂合性缺失 54.5%。DOK2(-)患者更有可能发生复发，5 年总生存率（59.1%）低于 DOK2(+)患者（76.4%，P=0.0403）。多因素分析确定 pT（危险比[HR]=2.748，95%置信区间[95%CI]=1.061-8.927，P=0.0361）、pN（HR=2.486，95%CI=1.264-4.932，P=0.0086）和 DOK2(-)（HR=2.343，95%CI=1.211-4.727，P=0.0112）是影响生存的显著和独立因素。
本研究数据表明，DOK2 可能是胃癌根治性切除术后患者预后不良的标志物。
