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Hiromichi Miyagaki MD, Makoto Yamasaki MD, PhD, Tsuyoshi Takahashi MD, PhD, Yukinori Kurokawa MD, PhD, Hiroshi Miyata MD, PhD, Kiyokazu Nakajima MD, PhD, FACS, Shuji Takiguchi MD, PhD, Yoshiyuki Fujiwara MD, PhD, Masaki Mori MD, PhD, FACS, Yuichiro Doki MD, PhD
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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.
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