Glutathione-S-transferase P1, T1 and M1 genetic polymorphisms in neoadjuvant-treated locally advanced gastric cancer: GSTM1-present genotype is associated with better prognosis in completely resected patients.
OBJECTIVE
Neoadjuvant chemotherapy in gastric cancer is now standard in the Western world; however, only 30-40% of the patients respond to induction therapy. Pretherapeutic predictors of response and prognosis would be of utmost interest to individualize treatment. Glutathione-S-transferase enzymes detoxify therapeutic drugs such as platin derivates and may influence outcome of the treated patients. Therefore, glutathione-S-transferase (GST) polymorphisms were assessed as predictive markers in cisplatinum-based neoadjuvant-treated gastric cancer.


METHODS
DNA was isolated from 139 patients with locally advanced gastric cancer (cT3/4 anyN cM0) before chemotherapy. Multiplex polymerase chain reaction was used for GSTT1 and GSTM1 genes, and allelic discrimination assay with the TaqMan system for the GSTP1 gene.


RESULTS
One hundred ten patients could be analyzed for GSTT1 (T-:23; T+87), 112 for GSTM1 (M-:52; M+:60) and 132 for GSTP1 (Ile/Ile: 55; Ile/Val: 59; Val/Val: 18). There was no significant correlation between any of the GSTT1, GSTM1, or GSTP1 genotypes and patients' characteristics or histopathological data; only the GSTM1+ genotype was associated with the non-intestinal subtype of the Lauren classification (p=0.045). GSTT1, GSTM1, and GSTP1 genotypes were not correlated with response to chemotherapy (p=0.57, p=0.38, p=0.33). In R0 resected patients, we found an improved survival for patients with the GSTM1-present genotype compared to patients with the GSTM1-null genotype (p=0.017). Moreover, the GSTM1-present genotype showed a significantly better tumor-related (p=0.017) and disease-free survival (p=0.029).


CONCLUSIONS
None of the common GST polymorphisms predicts response in our study, but the GSTM1+ genotype was associated with a better prognosis in completely resected patients. Further investigations on chemotherapy-associated gene polymorphisms are warranted.
Ott
Katja
K
Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. katja.ott@med.uni-heidelberg.de
Lordick
Florian
F
Becker
Karen
K
Ulm
Kurt
K
Siewert
JörgRüdiger
J
Höfler
Heinz
H
Keller
Gisela
G
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005743:Gastrectomy; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008197:Lymph Node Excision; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000628:therapy
D000970:Antineoplastic Agents; D002945:Cisplatin; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human