New molecular staging with G-factor supplements TNM classification in gastric cancer: a multicenter collaborative research by the Japan Society for Gastroenterological Carcinogenesis G-Project committee

Abstract

Background: The G-Project committee was erected by the Japan Society for Gastroenterological Carcinogenesis with an aim of establishing a new classification scheme based on molecular biological characteristics that would supplement the conventional TNM classification to better predict outcome.

Methods: In a literature search involving 822 articles on gastric cancer, eight molecules including p53, vascular endothelial growth factor (VEGF)-A, VEGF-C, matrix metalloproteinase-7 (MMP-7), human epidermal growth factor receptor 2, Regenerating islet-derived family, member 4, olfactomedin-4 and Claudin-18 were selected as candidates to be included in the new molecular classification scheme named G-factor. A total of 210 cases of gastric cancer who underwent curative R0 resection were registered from four independent facilities. Immunohistochemical staining for the aforementioned molecules was performed for the surgically resected specimens of the 210 cases to investigate the correlation between clinicopathological factors and expression of each molecule.

Results: No significant correlation was observed between the immunostaining expression of any of the eight factors and postoperative recurrence. However, the expressions of p53 and MMP-7 were significantly correlated with overall survival (OS). When 210 gastric cancer patients were divided into three groups based on the expression of p53 and MMP-7 (G0 group: negative for both p53 and MMP-7, n = 69, G1 group: positive for either p53 or MMP-7, n = 97, G2 group: positive for both of the molecules, n = 44), G2 group demonstrated significantly higher recurrence rate (59%) compared to 38% in G0 (p = 0.047). The multivariate regression analysis revealed that G2 group was independently associated with a shorter disease-free survival (DFS) (hazard ratio 1.904, 95% CI 1.098-3.303; p = 0.022), although the association with OS was not significant. Stage II patients among the G2 group had significantly inferior prognosis both in terms of OS and DFS when compared with those among the G0/G1 group, with survival curves similar to those of Stage III cases.

Conclusions: G-factor based on the expression of p53 and MMP-7 was found to be a promising factor to predict outcome of Stage II/III gastric cancer, and possibly to help select the treatment for Stage II cancer, thus supplementing the conventional TNM system.

Fig. 1

Immunohistochemical findings of p53, VEGF-A, VEGF-C, Reg IV, olfactomedin 4, Claudin-18, MMP7, and HER2

Fig. 2

Overall survival curves (a) and disease-free survival curves (b) of 210 total gastric cancer cases

Fig. 3

Overall survival curves (a) and disease-free survival curves (b) of 104 gastric cancer cases at Stage II

Fig. 4

Kaplan–Meier survival curve of patients with gastric cancer in combination with p53 and MMP7 expression (G0–2). Overall survival curves (a) and disease-free survival curves (b)