Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy.
BACKGROUND
Lung cancer is commonly treated with platinum compounds. The "glutathione pathway" participates in the metabolism of platinum compounds. We set out to test the hypotheses that single nucleotide polymorphisms (SNPs) or copy number polymorphisms for genes within the glutathione pathway might influence survival in lung cancer patients treated with these drugs.


METHODS
Germline DNA samples from 973 lung cancer patients were genotyped for 290 glutathione pathway SNPs. GSTT1 copy number was also assayed. We determined the association of these polymorphisms with survival for lung cancer patients, followed by functional genomic validation.


RESULTS
We observed suggestive associations between survival and GSTT1 copy number (P = 0.017), and GSTA5, GSTM4, and ABCC4 SNPs, adjusted for covariates (P = 0.018, 0.002, and 0.002, respectively) or not (P = 0.005, 0.011, and 0.002). One hundred lymphoblastoid cell lines were then treated with cisplatin, and IC(50) values were significantly associated with the GSTM4 SNP (P = 0.019). Furthermore, GSTM4, GSTT1, and ABCC4 overexpression significantly decreased cisplatin sensitivity in lung cancer and HEK293T cell lines.


CONCLUSIONS
These results suggest that GSTM4 polymorphisms are biomarkers for the prediction of cisplatin response. ABCC4 polymorphisms, as well as GSTT1 copy number, may also help to predict cisplatin response, but further validation is required. These results represent a step toward the individualized chemotherapy of lung cancer.
Moyer
Ann M
AM
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Sun
Zhifu
Z
Batzler
Anthony J
AJ
Li
Liang
L
Schaid
Daniel J
DJ
Yang
Ping
P
Weinshilboum
Richard M
RM
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D018628:Gene Dosage; D005978:Glutathione / Q000235:genetics* / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics
D000970:Antineoplastic Agents; D002945:Cisplatin; D005978:Glutathione; D005982:Glutathione Transferase; D007527:Isoenzymes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human; C413545:glutathione S-transferase T1; C514654:GSTM4 protein, human; C119995:glutathione S-transferase alpha