Clinical Research Papers:

TOP2A, GGH, and PECAM1 are associated with hematogenous, lymph node, and peritoneal recurrence in stage II/III gastric cancer patients enrolled in the ACTS-GC study

Masanori Terashima _, Wataru Ichikawa, Atsushi Ochiai, Koji Kitada, Issei Kurahashi, Shinichi Sakuramoto, Hitoshi Katai, Takeshi Sano, Hiroshi Imamura, Mitsuru Sasako and for the ACTS-GC Group

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Oncotarget. 2017; 8:57574-57582. https://doi.org/10.18632/oncotarget.15895

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Masanori Terashima1,*, Wataru Ichikawa2,*, Atsushi Ochiai3, Koji Kitada4, Issei Kurahashi5, Shinichi Sakuramoto6, Hitoshi Katai7, Takeshi Sano8, Hiroshi Imamura9, and Mitsuru Sasako10; for the ACTS-GC Group

1 Division of Gastric Surgery, Shizuoka Cancer Center, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan

2 Division of Medical Oncology, Showa University Fujigaoka Hospital, Kanagawa, Japan

3 Division of Pathology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, Japan

4 Department of Surgery, National Hospital Organization Fukuyama Medical Center, Okinogami-cho, Fukuyama, Hiroshima, Japan

5 Data Innovation Center, iAnalysis LLC, Minamiaoyama, Minato-ku, Tokyo, Japan

6 Department of Surgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Saitama, Japan

7 Gastric Surgery Division, National Cancer Center Hospital, Tsukiji, Chuo, Tokyo, Japan

8 Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Koto-Ku, Tokyo, Japan

9 Department of Surgery, Toyonaka Municipal Hospital, Shibahara-cho, Toyonaka, Osaka, Japan

10 Department of Surgery, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan

* These authors have contributed equally to this work

Correspondence to:

Masanori Terashima, email:

Keywords: stomach neoplasm, DNA topoisomerase II alpha, gamma-glutamyl hydrolase, CD31

Received: September 24, 2016 Accepted: February 12, 2017 Published: March 04, 2017


Background: To identify factors related to relapse sites, we carried out an exploratory biomarker analysis of data from the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer study, which is a randomized, controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer.

Patients and Methods: Surgical specimens from 829 patients were retrospectively examined, and 63 genes involved in a variety of biological processes were analyzed by quantitative real-time PCR. Gene expression normalized to reference genes was categorized as lower or higher than the median, and association with relapse sites was analyzed based on 5-year relapse-free survival.

Results: Hematogenous, lymph node, and peritoneal recurrence developed in 72, 105, and 138 of the 829 patients, respectively; hazard ratios were 0.79 (95% confidential interval: 0.54–1.16), 0.51 (0.31–0.82), and 0.60 (0.42–0.84), respectively. Expression of platelet/endothelial cell adhesion molecule 1 (PECAM1) and topoisomerase II alpha (TOP2A) was strongly correlated with hematogenous recurrence and peritoneal recurrence, respectively (false discovery rate = 7.7×10-5 and 0.002, respectively). Gamma-glutamyl hydrolase (GGH) expression was moderately correlated with lymph node recurrence (false discovery rate = 0.34). Relapse-free survival was worse in patients expressing high levels of PECAM1 (hazard ratio = 2.37, 1.65–3.41), TOP2A (hazard ratio = 2.35, 1.55–3.57), or GGH (hazard ratio = 1.87, 1.13–3.08), respectively. A multivariate analysis revealed that these were stronger independent risk factors than tumor histological type.

Conclusion: In patients with stage II/III gastric cancer, TOP2A, GGH, and PECAM1 levels in primary tumors are linked to high risk of hematogenous, lymph node, and peritoneal recurrence, respectively.

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