PURPOSE: We examined the pattern of single-nucleotide polymorphisms (SNPs) of gemcitabine metabolism-related and target genes in breast cancer patients and evaluated their association with drug response or toxicity. PATIENTS AND METHODS: SNPs in deoxycytidine kinase (dCK), deoxycytidine monophosphate deaminase (DCTD), and ribonucleotide reductase M1 polypeptide (RRM1) were analyzed with genomic DNA of 10 breast cancer cell lines, 74 peripheral blood mononuclear cell (PBMC) samples from advanced breast cancer patients treated with gemcitabine, and 56 PBMC samples from healthy volunteers. RESULTS: The incidences of SNPs of breast cancer patients were 1.4% in dCK (626 A>G), 10.8% in DCTD (315 T>C), 40.5% in the first RRM1 (1082 C>A), 44.6% in the second RRM1 (2455 A>G), 44.6% in the third RRM1 (2464 G>A), and 23% in two RRM1 sites (2455 A>G and 2464 G>A) that were similar to those of the normal control group. We found a double SNP of RRM1 (2455 A>G and 2464 G>A) to be the novel haplotype that was associated with a lower frequency of chemotherapy-induced toxicity, such as neutropenia (p < .01) and G-CSF requirement (p < .005). CONCLUSION: RRM1 haplotype showed an association with susceptibility to gemcitabine monotherapy in breast cancer patients.
PURPOSE: We examined the pattern of single-nucleotide polymorphisms (SNPs) of gemcitabine metabolism-related and target genes in breast cancerpatients and evaluated their association with drug response or toxicity. PATIENTS AND METHODS: SNPs in deoxycytidine kinase (dCK), deoxycytidine monophosphate deaminase (DCTD), and ribonucleotide reductase M1 polypeptide (RRM1) were analyzed with genomic DNA of 10 breast cancer cell lines, 74 peripheral blood mononuclear cell (PBMC) samples from advanced breast cancerpatients treated with gemcitabine, and 56 PBMC samples from healthy volunteers. RESULTS: The incidences of SNPs of breast cancerpatients were 1.4% in dCK (626 A>G), 10.8% in DCTD (315 T>C), 40.5% in the first RRM1 (1082 C>A), 44.6% in the second RRM1 (2455 A>G), 44.6% in the third RRM1 (2464 G>A), and 23% in two RRM1 sites (2455 A>G and 2464 G>A) that were similar to those of the normal control group. We found a double SNP of RRM1 (2455 A>G and 2464 G>A) to be the novel haplotype that was associated with a lower frequency of chemotherapy-induced toxicity, such as neutropenia (p < .01) and G-CSF requirement (p < .005). CONCLUSION:RRM1 haplotype showed an association with susceptibility to gemcitabine monotherapy in breast cancerpatients.
Authors: Maria L Alvarellos; Jatinder Lamba; Katrin Sangkuhl; Caroline F Thorn; Liewei Wang; Daniel J Klein; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2014-11 Impact factor: 2.089