Combined GADD45A and thymidine phosphorylase expression levels predict response and survival of neoadjuvant-treated gastric cancer patients.
OBJECTIVE
We evaluated the expression of seven therapy-related genes to predict the clinical outcome of advanced gastric cancer patients treated with a neoadjuvant chemotherapeutic protocol.


METHODS
Pretherapeutic, formalin-fixed, and paraffin-embedded biopsies of 61 patients, who received a 5-fluorouracil (5-FU)- and cisplatin-based chemotherapy were studied. The expressions of the 5-FU-related genes TS, DPD, and TP and of the cisplatin-related genes ERCC1, ERCC4, KU80, and GADD45A were analyzed by quantitative real-time PCR. The expression levels of single genes and of various combinations were tested for an association with response and overall survival.


RESULTS
High DPD levels were more frequently found in nonresponding patients and were associated with worse survival. GADD45A and TP levels showed weak associations with response, but GADD45A expression correlated with survival. There was no association with response for TS expression, but tumors with a high TS level were associated with worse survival. The combination of GADD45A and TP revealed the strongest predictive effect. High expression values of TP and/or GADD45A were exclusively found in nonresponding patients (P = 0.002) and were associated with a significantly poorer survival (P = 0.04).


CONCLUSIONS
Combined gene expression levels of TP and GADD45A represent a new variable to predict the clinical outcome after neoadjuvant chemotherapy in gastric cancer. The association of DPD expression with response and survival underlines a predominant role of DPD to predict 5-FU sensitivity. The association of TS expression levels with survival but not with response suggests an importance of this gene for tumor progression.
Napieralski
Rudolf
R
Department of Pathology, Technische Universität München, Munich, Germany.
Ott
Katja
K
Kremer
Markus
M
Specht
Katja
K
Vogelsang
Holger
H
Becker
Karen
K
Müller
Martina
M
Lordick
Florian
F
Fink
Ulrich
U
Rüdiger Siewert
Jörg
J
Höfler
Heinz
H
Keller
Gisela
G
D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009687:Nuclear Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000235:genetics*; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome; D000097642:GADD45 Proteins
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D002945:Cisplatin; D004268:DNA-Binding Proteins; D042943:Dihydrouracil Dehydrogenase (NADP); D004720:Endonucleases; D005472:Fluorouracil; D000072200:Ku Autoantigen; D009687:Nuclear Proteins; D012333:RNA, Messenger; D013939:Thymidine Phosphorylase; D013940:Thymidylate Synthase; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; C000606509:Xrcc6 protein, human