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.
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.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan, t_sawada@osaka-ekisaikai.jp.
Tetsuji
T
Sawada
Masakazu
M
Yashiro
Kazuhiro
K
Sentani
Naohide
N
Oue
Wataru
W
Yasui
Kohji
K
Miyazaki
Keita
K
Kai
Sachio
S
Fushida
Takashi
T
Fujimura
Masaichi
M
Ohira
Yoshihiro
Y
Kakeji
Shoji
S
Natsugoe
Ken
K
Shirabe
Sachiyo
S
Nomura
Yutaka
Y
Shimada
Naohiro
N
Tomita
Kosei
K
Hirakawa
Yoshihiko
Y
Maehara
D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D057167:Claudins / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012958:Societies, Scientific; D013274:Stomach Neoplasms / Q000145:classification / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
D014408:Biomarkers, Tumor; D057167:Claudins; D020783:Matrix Metalloproteinase 7; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C486683:CLDN18 protein, human; C467484:VEGFA protein, human; C508053:ERBB2 protein, human; C060932:MMP7 protein, human