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• W2094643876 abstract "Identifying patients prior to treatment who are more likely to benefit from chemotherapeutic agents or more likely to experience adverse events is an aim of personalized medicine. Pharmacogenomics offers a potential means of achieving this goal through the discovery of predictive germline genetic biomarkers. When applied particularly to the treatment of head and neck cancers, such information could offer significant benefit to patients as a means of potentially reducing morbidity associated with platinum-based chemotherapy. We developed a genome-wide, cell-based approach to identify single nucleotide polymorphisms (SNPs) associated with platinum susceptibility and then evaluated these SNPs as predictors for response and toxicity in head and neck cancer patients treated with platinum-based therapy as part of a phase II clinical trial. Sixty head and neck cancer patients were evaluated. Of 45 genome-wide SNPs examined, we found that 2 SNPs, rs6870861 (P = 0.004; false discovery rate [FDR] < 0.05) and rs2551038 (P = 0.005; FDR < 0.05), were associated significantly with overall response to carboplatin-based induction chemotherapy when incorporated into a model along with total carboplatin exposure. Interestingly, these 2 SNPs are associated strongly with the baseline expression of >20 genes (all P ≤ 10–4), and that 2 genes (SLC22A5 and SLCO4C1) are important organic cation/anion transporters known to affect platinum uptake and clearance. Several other SNPs were associated nominally with carboplatin-related hematologic toxicities. These findings demonstrate importantly that a genome-wide, cell-based model can identify novel germline genetic biomarkers of platinum susceptibility, which are replicable in a clinical setting with treated cancer patients and seem clinically meaningful for potentially enabling future personalization of care in such patients. Identifying patients prior to treatment who are more likely to benefit from chemotherapeutic agents or more likely to experience adverse events is an aim of personalized medicine. Pharmacogenomics offers a potential means of achieving this goal through the discovery of predictive germline genetic biomarkers. When applied particularly to the treatment of head and neck cancers, such information could offer significant benefit to patients as a means of potentially reducing morbidity associated with platinum-based chemotherapy. We developed a genome-wide, cell-based approach to identify single nucleotide polymorphisms (SNPs) associated with platinum susceptibility and then evaluated these SNPs as predictors for response and toxicity in head and neck cancer patients treated with platinum-based therapy as part of a phase II clinical trial. Sixty head and neck cancer patients were evaluated. Of 45 genome-wide SNPs examined, we found that 2 SNPs, rs6870861 (P = 0.004; false discovery rate [FDR] < 0.05) and rs2551038 (P = 0.005; FDR < 0.05), were associated significantly with overall response to carboplatin-based induction chemotherapy when incorporated into a model along with total carboplatin exposure. Interestingly, these 2 SNPs are associated strongly with the baseline expression of >20 genes (all P ≤ 10–4), and that 2 genes (SLC22A5 and SLCO4C1) are important organic cation/anion transporters known to affect platinum uptake and clearance. Several other SNPs were associated nominally with carboplatin-related hematologic toxicities. These findings demonstrate importantly that a genome-wide, cell-based model can identify novel germline genetic biomarkers of platinum susceptibility, which are replicable in a clinical setting with treated cancer patients and seem clinically meaningful for potentially enabling future personalization of care in such patients. R. Stephanie Huang, PhD, is an Assistant Professor in the Department of Medicine, University of Chicago. Her article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, April 2010." @default.
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• W2094643876 date "2011-05-01" @default.
• W2094643876 modified "2023-10-17" @default.
• W2094643876 title "Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck cancers" @default.
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• W2094643876 doi "https://doi.org/10.1016/j.trsl.2011.01.005" @default.
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