Association of gastric and intestinal phenotypic marker expression of gastric carcinomas with tumor thymidylate synthase expression and response to postoperative chemotherapy with 5-fluorouracil.
OBJECTIVE
It is well known that both gastric and intestinal phenotypic markers are expressed in gastric carcinomas, irrespective of their histological type. In the present study, the associations among phenotypic marker expression of gastric carcinomas, tumor thymidylate synthase (TS) expression, and the chemotherapeutic response to 5-fluorouracil (5-FU) were examined.


METHODS
The gastric and intestinal phenotypic marker expression of the tumor was determined by the combination of the expression of human gastric mucin (HGM), MUC6, MUC2, and CD10, and was evaluated in comparison with tumor TS expression in 137 advanced gastric carcinomas in 137 patients (75 with postoperative chemotherapy with 5-FU and 62 without postoperative chemotherapy). Tumors were classified into the gastric- (G-), gastric and intestinal mixed- (GI-), intestinal- (I-), or unclassified- (UC-) phenotype according to the immunopositivity of HGM, MUC6, MUC2, and CD10 stainings. The associations among the gastric and intestinal phenotypic marker expression of the tumor, tumor TS expression, effect of postoperative chemotherapy with 5-FU, and the patient's prognosis were examined.


RESULTS
Of the 137 gastric carcinomas, 48 (35.0%), 58 (42.3%), 23 (16.8%), and 8 (5.8%)were classified as the G-, GI-, I- and UC-phenotype, respectively. The high TS expression of more than 25% tumor cell positivity was found in 25 (52.1%) of the 48 G-phenotype tumors, 39 (67.2%) of the 58 GI-phenotype tumors, 18 (78.3%) of the 23 I-phenotype tumors, and 4 (50.0%) of the 8 UC-phenotype tumors. The I-phenotype tumors were significantly correlated with the higher rate of the high TS expression as compared with the G-phenotype tumors (P<0.05). Among 48 patients with the G-phenotype tumor, the 5-year survival rate in patients with and without postoperative chemotherapy was 39.7 and 27.8%, respectively. The patients with postoperative chemotherapy had a significantly better prognosis than those without postoperative chemotherapy (P<0.05). Conversely, there were no significant correlations between the presence of postoperative chemotherapy and the patient's prognosis among patients with GI-, I-, and UC-phenotype tumors.


CONCLUSIONS
These results indicate that postoperative chemotherapy with 5-FU could be effective for patients with the G-phenotype tumor, since the incidence of intratumoral expression of TS, the target enzyme of 5-FU, is significantly low in G-phenotype tumors.
Department of Surgery, Toyosu Hospital, Showa University, 1-18, Toyosu 4 chome, Koto-ku, 135-8577 Tokyo, Japan.
Yusuke
Y
Tajima
Tadakazu
T
Shimoda
Yukihiro
Y
Nakanishi
Noboru
N
Yokoyama
Takayuki
T
Tanaka
Kouji
K
Shimizu
Toyohiko
T
Saito
Masatoshi
M
Kawamura
Mitsuo
M
Kusano
Kazuhide
K
Kumagai
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005743:Gastrectomy; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007422:Intestines / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D013274:Stomach Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D013940:Thymidylate Synthase / Q000032:analysis*; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D013940:Thymidylate Synthase; D005472:Fluorouracil