Li, Liang

Abstract 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 IC50 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. Cancer Epidemiol Biomarkers Prev; 19(3); 811–21

Abstract Two cytidine analogues, gemcitabine (dFdC) and 1-β-d-arabinofuranosylcytosine (AraC), show significant therapeutic effect in a variety of cancers. However, response to these drugs varies widely. Evidence from tumor biopsy samples shows that expression levels for genes involved in the cytidine transport, metabolism, and bioactivation pathway contribute to this variation in response. In the present study, we set out to test the hypothesis that variation in gene expression both within and outside of this “pathway” might influence sensitivity to gemcitabine and AraC. Specifically, Affymetrix U133 Plus 2.0 GeneChip and cytotoxicity assays were performed to obtain basal mRNA expression and IC50 values for both drugs in 197 ethnically defined Human Variation Panel lymphoblastoid cell lines. Genes with a high degree of association with IC50 values were involved mainly in cell death, cancer, cell cycle, and nucleic acid metabolism pathways. We validated selected significant genes by performing real-time quantitative reverse transcription-PCR and selected two representative candidates, NT5C3 (within the pathway) and FKBP5 (outside of the pathway), for functional validation. Those studies showed that down-regulation of NT5C3 and FKBP5 altered tumor cell sensitivity to both drugs. Our results suggest that cell-based model system studies, when combined with complementary functional characterization, may help to identify biomarkers for response to chemotherapy with these cytidine analogues. [Cancer Res 2008;68(17):7050–8]