ATP-binding Cassette Subfamily C Member 4 Research Articles

A polymorphism in ABCC4 is related to efficacy of 5-FU/capecitabine-based chemotherapy in colorectal cancer patients

To investigate the association of microRNA (miRNA) binding-site polymorphisms in the drug transporter genes with the efficacy of 5-Fluorouracil (5-FU)/capecitabine-based chemotherapy in colorectal cancer (CRC), 6 polymorphisms were determined in 432 CRC patients by using DNA sequencing method. The impacts of the polymorphisms on the miRNA-mediated regulation of gene expression were evaluated by using the methods including quantitative real-time PCR, western blotting, and luciferase reporter assays. The effects of miRNA on the intracellular concentration and cytotoxicity of 5-FU in CRC cells were measured by high performance liquid chromatography conjected tandem mass spectrometry (HPLC-MS/MS) and MTT methods, respectively. Statistical analysis showed that a polymorphism rs3742106 in the 3′-UTR of ATP-binding cassette subfamily C member 4 (ABCC4) gene was significantly associated with the efficacy of 5-FU/capecitabine-based chemotherapy in CRC. The patients with T/T genotype had significantly higher response rate than those with G/G and G/T genotypes. The expression of ABCC4 was inhibited by miR-3190-5p through binding to the 3′-UTR of the ABCC4 gene. This regulatory role of miR-3190-5p was disrupted by rs3742106. Furthermore, we found that the intracellular concentration of 5-FU was elevated by miR-3190-5p, and consequently the sensitivity of CRC cells to 5-FU was also enhanced. Rs3742106 might be regarded as a genetic biomarker for individualized use of 5-FU and capecitabine in CRC.

ABCC4 functional SNP in the 3' splice acceptor site of exon 8 (G912T) is associated with unfavorable clinical outcome in children with acute lymphoblastic leukemia.

ATP-binding cassette subfamily C member 4 (ABCC4) encoding MRP4 protein is involved in pediatric acute lymphoblastic leukemia (ALL) drug resistance. The nonsynonymous single nucleotide polymorphism (SNP) rs2274407 (G912T; K304N) is located in the 3' splice acceptor site of exon 8 of ABCC4 pre-mRNA. The aim of this study was to investigate the prognostic value of rs2274407 in childhood ALL and its possible functional effect on MRP4. ABCC4 G912T SNP was genotyped in 145 Iranian Philadelphia-negative (Ph-) children with ALL using modified tetra-primer ARMS PCR and evaluated for possible association with 3-year disease-free survival (3DFS). In addition, functional impact of rs2274407 on the MRP4 activity and possible post-transcriptional modifications were bioinformatically and experimentally studied. ABCC4 912T allele carriers (G/T and T/T genotypes) are associated with worse 3DFS in Pre-B cell ALL [P=0.00019, OR (95% CI)=13.17 (2.55-68.11)]. In addition, computational studies showed that K304N alteration has no impact on the MRP4 activity. However, it may disrupt the normal splicing process of ABCC4 pre-mRNA. To date, this is the first study that shows the potential functional impact of rs2274407 SNP on the aberrant splicing of ABCC4 mRNA. We also demonstrated a robust association between G912T and pediatric ALL negative outcome, which may be explained by the novel computational studies performed in this study.

MiR-133b down-regulates ABCC1 and enhances the sensitivity of CRC to anti-tumor drugs.

Multidrug resistance (MDR) is the main cause of failed chemotherapy treatments. Therefore, preventing MDR is pivotal in treating colorectal cancer (CRC). In a previous study miR-133b was shown to be a tumor suppressor. Additionally, in CRC cells transfected with miR-133b, ATP-binding cassette (ABC) subfamily C member 1(ABCC1) was shown to be significantly down regulated. Whether miR-133b also enhances the chemosensitivity of drugs used to treat CRC by targeting ABCC1 is still unclear. Here, we utilized flow cytometry and high-performance liquid chromatography (HPLC) analysis to identify the ability of miR-133b to reserve MDR in CRC. We then used a dual-luciferase reporter assay to validate that miR-133b targets ABCC1. Further in vivo experiments were designed to validate the method in which miR-133b reversed MDR in CRC cells. The results demonstrated that the level of miR-133b was down-regulated and the expression of ABCC1 was up-regulated in drug-resistant CRC cells compared to non-drug-resistant CRC cells. The restoration of miR-133b expression in CRC drug-resistant cells in vitro resulted in reduced IC50s to chemotherapeutic drugs, significantly induced G1 accumulation, inhibited growth and promoted necrosis in combination with either 5-fluorouracil (5-FU) or vincristine (VCR), and decreased the expression of ABCC1. The dual-luciferase assay demonstrated that miR-133b directly targets ABCC1. The combination of agomiRNA-133b with chemotherapeutic drugs in vivo inhibited tumor growth induced by CRC drug-resistant cells. A xenograft from the in vivo model resulted in up-regulated levels of miR-133b and down-regulated levels of ABCC1. Therefore, miR-133b enhances the chemosensitivity of CRC cells to anti-tumor drugs by directly down-regulating ABCC1. This discovery provides a therapeutic strategy in which miR-133b is used as a potential sensitizer for drug-resistant CRC.

Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis

BackgroundAntiepileptic drugs (AEDs) are effective medications available for epilepsy. However, many patients do not respond to this treatment and become resistant. Genetic polymorphisms may be involved in the variation of AEDs response. Therefore, we conducted an updated systematic review and a meta-analysis to investigate the contribution of the genetic profile on epilepsy drug resistance.MethodsWe proceeded to the selection of eligible studies related to the associations of polymorphisms with resistance to AEDs therapy in epilepsy, published from January 1980 until November 2016, using Pubmed and Cochrane Library databases. The association analysis was based on pooled odds ratios (ORs) and 95% confidence intervals (CIs).ResultsFrom 640 articles, we retained 13 articles to evaluate the relationship between ATP-binding cassette sub-family C member 1 (ABCB1) C3435T polymorphism and AEDs responsiveness in a total of 454 epileptic AEDs-resistant cases and 282 AEDs-responsive cases. We found a significant association with an OR of 1.877, 95% CI 1.213–2.905. Subanalysis by genotype model showed a more significant association between the recessive model of ABCB1 C3435T polymorphism (TT vs. CC) and the risk of AEDs resistance with an OR of 2.375, 95% CI 1.775–3.178 than in the dominant one (CC vs. TT) with an OR of 1.686, 95% CI 0.877–3.242.ConclusionOur results indicate that ABCB1 C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy. As genetic screening of this genotype may be useful to predict AEDs response before starting the treatment, further investigations should validate the association.

ATP-binding cassette sub-family C member 4 (ABCC4) is overexpressed in human NK/T-cell lymphoma and regulates chemotherapy sensitivity: Potential as a functional therapeutic target

Nasal-type natural killer/T-cell (NK/T-cell) lymphomas are subtypes of non-Hodgkin’s lymphoma (NHL), which are typically more clinically aggressive. There is, however relatively little understanding of nasal-type NK/T-cell lymphoma molecular pathogenesis. Thus, in this study we applied RNA sequencing to systematically screen for altered gene expression in human NK/T-cell lymphoma cell lines YTS and SNK-6 versus normal NK cells. We found that ATP-binding cassette sub-family C Member 4 (ABCC4) levels were significantly upregulated both in human NK/T-cell lymphoma YTS and SNK-6 cells, as compared with normal NK cells. These expression levels were further confirmed by real-time PCR. Protein levels of ABCC4 were also significantly higher in YTS and SNK-6 cells as compared with normal NK cells. Clinically relevant, ABCC4 expression levels were significantly higher in human NK/T-cell lymphoma tissues as compared with control nasal mucosa tissues, confirmed by immunohistochemical staining. In addition, we explored the biological function of such ABCC4 upregulation. Overexpression of ABCC4 by lentivirus transfection induced chemotherapy resistance to epirubicin (EPI) and cisplatin (DDP) in YTS cells. In contrast, knockdown of ABCC4 expression by shRNA contributed to chemotherapy sensitivity by both EPI and DDP. Furthermore, overexpression of ABCC4 inhibited, while downregulation of ABCC4 increased, YTS cell apoptosis following treatment by EPI or DDP. Therefore, the present study identified ABCC4 to be overexpressed in human NK/T-cell lymphoma cells, to regulate chemotherapy sensitivity to EPI and DDP, and possibly to be a functional therapeutic target. These findings may provide a basic rationale for new approaches in the effort to develop anti-tumor therapeutics for NK/T-cell lymphoma.

Candidate pathway-based genetic association study of platinum and platinum–taxane related toxicity in a cohort of primary lung cancer patients

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect. Patients and methodsWe studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways. ResultsPatients who had diabetes mellitus were more likely to have CIPN (p=0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p=0.0004) and type of concurrent chemotherapy (p<0.001). SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms. ConclusionsEpidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients.

Silencing of the ABCC4 gene by RNA interference reverses multidrug resistance in human gastric cancer.

The identification of genes associated with recurrent drug resistance in gastric cancer and the elucidation of the underlying molecular mechanisms associated with recurrent drug resistance in gastric cancer are important for the effective treatment and prognosis of this cancer. Variations in the expression level of the ATP-binding cassette subfamily C member 4 (ABCC4) gene are correlated with the recurrence, development and chemotherapeutic susceptibility of various types of cancers. In the present study, we demonstrated that the ABCC4 gene was highly expressed in multiple types of gastric cancer cells, and ABCC4 expression was even more prominent in the drug-resistant gastric cancer cells. Conversely, in normal gastric mucosal cells, ABCC4 expression was very low or undetectable. We used RNA interference to decrease the expression of ABCC4 in drug-resistant gastric cancer cells, which resulted in an increase in apoptosis and cell cycle arrest in the G1 phase. In addition, we found that ABCC4 knockdown in 5-fluorouracil (5-FU)-resistant cancer cells restored 5-FU sensitivity, resulting in the inhibition of cell proliferation and tumour growth in nude mice. Our results showed that inhibition of ABCC4 gene expression can inhibit the proliferation of multidrug-resistant gastric cancer cells and can enhance gastric cancer cell sensitivity to chemotherapeutic drugs.

Mithramycin A sensitizes therapy-resistant breast cancer stem cells toward genotoxic drug doxorubicin

Chemotherapy resistance is a major clinical challenge for the management of locally advanced breast cancer. Accumulating evidence suggests a major role of cancer stem cells (CSCs) in chemoresistance evoking the requirement of drugs that selectively target CSCs in combination with chemotherapy. Here, we report that mithramycin A, a known specificity protein (Sp)1 inhibitor, sensitizes breast CSCs (bCSCs) by perturbing the expression of drug efflux transporters, ATP-binding cassette sub-family G, member 2 (ABCG2) and ATP-binding cassette sub-family C, member 1 (ABCC1), survival factors, B-cell lymphoma 2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and, stemness regulators, octamer-binding transcription factor 4 (Oct4) and Nanog, which are inherently upregulated in these cells compared with the rest of the tumor population. In-depth analysis revealed that aberrant overexpression of Sp1 in bCSCs transcriptionally upregulates (1) resistance-promoting genes to protect these cells from genotoxic therapy, and (2) stemness regulators to sustain self-renewal potential of these cells. However, mithramycin A causes transcriptional suppression of these chemoresistant and self-renewal genes by inhibiting Sp1 recruitment to their promoters. Under such antisurvival microenvironment, chemotherapeutic agent doxorubicin induces apoptosis in bCSCs via DNA damage-induced reactive oxygen species generation. Cumulatively, our findings raise the possibility that mithramycin A might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to eliminate CSCs. This will consequently lead to the improvement of therapeutic outcome for the treatment-resistant breast carcinomas.

Prognostic Significance and Molecular Mechanism of ATP-Binding Cassette Subfamily C Member 4 in Resistance to Neoadjuvant Radiotherapy of Locally Advanced Rectal Carcinoma

BackgroundMechanism of radioresistance in rectal carcinoma remains largely unknown. We aimed to evaluate the predictive role of ATP-binding cassette subfamily C member 4 (ABCC4) in locally advanced rectal carcinoma and explore possible molecular mechanisms by which ABCC4 confers the resistance to neoadjuvant radiotherapy.MethodsThe expression of ABCC4 and P53 mutant in biopsy tissue specimens from 121 locally advanced rectal carcinoma patients was examined using immunohistochemistry. The factors contributing to 3-year overall survival and disease-free survival were evaluated using the Kaplan-Meier method and Cox proportional hazard model. Lentivirus-mediated small hairpin RNA was applied to inhibit ABCC4 expression in colorectal carcinoma cell line RKO, and investigate the radiosensitivity in xenograft model. Intracellular cyclic adenosine monophosphate concentration and cell cycle distribution following irradiation were detected.ResultsHigh expression of ABCC4 and p53 mutant in pretreated tumors, poor pathological response, and high final tumor staging were significant factors independently predicted an unfavorable prognosis of locally advanced rectal carcinoma patients after neoadjuvant radiotherapy. Down-regulation of ABCC4 expression significantly enhanced irradiation-induced suppression of tumor growth in xenograft model. Furthermore, down-regulation of ABCC4 expression enhanced intracellular cyclic adenosine monophosphate production and noticeable deficiency of G1-S phase checkpoint in cell cycle following irradiation.ConclusionsOur study suggests that ABCC4 serves as a novel predictive biomarker that is responsible for the radioresistance and predicts a poor prognosis for locally advanced rectal carcinoma after neoadjuvant radiotherapy.

Abstract C217: Prognostic significance and molecular mechanism of ATP-Binding Cassette subfamily C member 4 in resistance to neoadjuvant radiotherapy of locally advanced rectal carcinoma.

Abstract Mechanism of radioresistance in rectal carcinoma remains largely unknown. The aim of this study is to verify the predictive value of ATP-Binding Cassette subfamily C member 4 (ABCC4) in locally advanced rectal carcinoma and explore possible molecular mechanisms by which ABCC4 confers the resistance to neoadjuvant radiotherapy. Methods: Expression of ABCC4 protein in pretreated biopsy tissue specimens from locally advanced rectal carcinoma patients was examined using immunohistochemistry. The 3-year overall survival and disease-free survival were used to determine long-term prognosis, and significant clinicopathological factors were identified by univariate log-rank test and multivariate Cox regression analysis. Lentivirus-mediated small hairpin RNA inhibited ABCC4 expression in colorectal carcinoma cell lines, and altered radiosensitivity was confirmed by xenograft model in vivo. Intracellular cyclic adenosine monophosphate concentration and cell cycle distribution following irradiation were further detected. Results: High expression of ABCC4 in pretreated tumors, p53 mutant type, high serum CEA and positive lymph node predicted an unfavorable postoperative prognosis for locally advanced rectal carcinoma patients after neoadjuvant radiotherapy in univariate analysis. Multivariate Cox regression analysis further demonstrated that high expression of ABCC4 and p53 mutant type were significant factors independently predicted an unfavorable long-term prognosis. Downregulation of ABCC4 expression significantly enhanced irradiation-induced suppression of tumor growth in xenograft model in vivo. Furthermore, inhibition of ABCC4 expression induced intracellular cyclic adenosine monophosphate accumulation and a noticeable deficiency of G1-S phase checkpoint in cell cycle following irradiation. Conclusions: Our study suggests ABCC4 as a novel predictive biomarker in predicting radioresistance and prognosis for locally advanced rectal carcinoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C217. Citation Format: Zhiqi Yu, Chang Zhang, Rui Chai, Yan Du, Xianhua Gao, Junjie Xing, Guangwen Cao, Chuangang Fu. Prognostic significance and molecular mechanism of ATP-Binding Cassette subfamily C member 4 in resistance to neoadjuvant radiotherapy of locally advanced rectal carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C217.

Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease

Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter-individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response. To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic-based therapeutic recommendations. We conducted a query on PubMed database using 'inflammatory bowel disease', 'thiopurine', 'azathioprine', '6-mercaptopurine', 'TPMT', 'pharmacogenetics', 'TDM', and selected relevant articles, especially clinical studies. Thiopurine metabolism - key enzyme: thiopurine S-methyltransferase (TPMT) - modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6-TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S-transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family C member 4 (ABCC4) are reviewed and discussed for clinical relevance. Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.

ABCC1 G2012T single nucleotide polymorphism is associated with patient outcome in primary neuroblastoma and altered stability of the ABCC1 gene transcript

Multidrug resistance is a major cause of treatment failure in neuroblastoma. Multidrug resistance protein 1 has been previously implicated in the development of drug resistance, particularly with regard to influencing clinical outcomes in neuroblastoma. Numerous single nucleotide polymorphisms (SNPs) in the gene encoding multidrug resistance protein 1, namely ATP-binding cassette sub-family C member 1 (ABCC1), have been identified, however, less is known about their potential association with patient outcome. Our aim was to determine the prognostic implications of ABCC1 polymorphisms in neuroblastoma. We assessed the frequency of four nonsynonymous ABCC1 SNPs, namely G128C, G1299T, G2168A, and G2012T in both neuroblastoma samples and normal cord blood cells. Polymorphism rates and associations with clinicopathologic characteristics were assessed. The initial three examined polymorphisms were found to be present at very low levels in the Australian population. Of 195 neuroblastoma samples and 158 cord blood samples, none carried the G2012T homozygous variant allele, whereas 13% were heterozygous. The presence of the variant allele was associated with an improved outcome in patients with aggressive neuroblastoma, particularly in older children (P<0.05) and those with nonmetastatic disease (P<0.005). Tumor cell lines that were heterozygous for this SNP, expressed the variant ABCC1 gene transcript at significantly lower levels than the wild-type ABCC1 transcript, and this was associated with the reduced mRNA stability of the variant transcript. Collectively, our findings indicated a potential prognostic role of the G2012T ABCC1 polymorphism in clinically relevant subsets of patients with neuroblastoma, and provided further evidence for the ABCC1 gene being a major determinant in neuroblastoma biology.

Polymorphisms in the Multiple Drug Resistance Protein 1 and in P-Glycoprotein 1 Are Associated with Time to Event Outcomes in Patients with Relapsed and/or Refractory Multiple Myeloma Treated with Bortezomib and Pegylated Liposomal Doxorubicin.

Abstract 109▪▪This icon denotes an abstract that is clinically relevant. Background:Single nucleotide polymorphisms (SNPs) in the gene encoding multiple drug resistance protein 1 (ATP-binding cassette, sub-family C member 1 (ABCC1) influence its ability to act as a mediator of anthracycline resistance. The same is true for SNPs in P-glycoprotein 1 (ATP-binding cassette, sub-family B member 1 (ABCB1)), and the latter have been associated with outcome in newly diagnosed patients with multiple myeloma treated with anthracycline-based therapy. We therefore sought to evaluate the role of SNPs in ABCC1 and ABCB1 in the outcome of patients with relapsed and/or refractory multiple myeloma. Methods:The DOXIL-MMY-3001 study was an international, randomized, phase III trial comparing the efficacy of single-agent bortezomib to that of bortezomib with pegylated liposomal doxorubicin (PLD) in patients with relapsed and/or refractory multiple myeloma. Patients treated with bortezomib received this proteasome inhibitor at 1.3 mg/m2 as an intravenous push on days 1, 4, 8, and 11 of every 21-day cycle, while patients on the combination arm received this dose and schedule of bortezomib along with PLD as an infusion at 30 mg/m2 on day 4. Genomic DNA samples were obtained from all subjects in the intention-to-treat cohort who consented to DNA testing under Part 1 of the pharmacogenomic component of the clinical trial protocol. Samples that produced at least one useable genotype were included in this pharmacogenomic analysis. SNPs in ABCC1 (R723Q) and ABCB1 (1236 C>T, 2677 G>W (W = T or A), and 3435 C>T) were correlated with the overall response rate (complete + partial), time to progression, progression-free survival, and overall survival. Results:Genetic transmission patterns differ among racial groups, and since usable genotype and clinical data were available for 301 subjects, 279 of whom were Caucasians, this analysis focused on that group. The ABCC1 gene polymorphism R723Q was not represented in the bortezomib arm, and found in 5 subjects (3.5%) who received bortezomib + PLD. Its presence was significantly associated with a longer time to progression (median of 330 days vs. 129 days; p = 0.0008), a longer progression-free survival (median of 338 days vs. 129 days p = 0.0006), and a superior overall survival (p = 0.0045) in these patients. The ABCB1 gene polymorphism at 3435 (C>T) was associated with progression-free survival (p = 0.0578), response rate (p = 0.0782) and time to progression (p = 0.0923) in patients receiving bortezomib + PLD, though not at the level of statistical significance, and no correlation was found in the bortezomib alone arm. However, in a recessive genetic model, the ABCB1 gene polymorphism at 3435 T allele was significantly associated with a better clinical outcome, specifically time to progression (p = 0.0405), and progression-free survival (p = 0.0186) in patients receiving bortezomib + PLD. Haplotype analysis indicated that the three most frequent haplotypes for ABCB1 may have been associated with response rate in subjects with relapsed multiple myeloma who received bortezomib + PLD treatment (p = 0.0775), though not at the level of statistical significance. Diplotypes that contained 3435T may have been associated with a superior time to progression (p = 0.0819) and progression-free survival (p = 0.0891) in subjects with relapsed multiple myeloma who received bortezomib + PLD when compared to the most frequent diplotype containing 3435C, though not at the level of statistical significance. Conclusions:These findings indicate a potential role for SNPs in both ABCC1 and ABCB1 in modulating the long-term outcome of patients with relapsed and/or refractory multiple myeloma treated with the combination of bortezomib + PLD. Moreover, they support additional prospective studies to determine if such data could be incorporated into an algorithm by which therapy in the relapsed and/or refractory setting could be tailored to each individual patient's own genetic make-up. Disclosures:Ricci:Centocor Ortho Biotech Inc.: Employment. Cohen:Johnson & Johnson Pharmaceutical Research and Development: Employment. Favis:Johnson & Johnson Pharmaceutical Research and Development: Employment. Huang:Centocor Ortho Biotech Inc.: Employment. Rackoff:Centocor Ortho Biotech Inc.: Employment. Zhuang:Centocor Ortho Biotech Inc.: Employment. Sonneveld:Centocor Ortho Biotech Inc.: Membership on an entity's Board of Directors or advisory committees.

Genetic Variation in Efflux Transporters Influences Outcome to Methotrexate Therapy in Patients with Psoriasis

Methotrexate, an inexpensive first-line systemic therapy for moderate-to-severe psoriasis, is limited in its use by unpredictable efficacy and toxicity. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in methotrexate transmembrane transporters and adenosine receptors are associated with efficacy and/or toxicity of the drug. DNA was collected from 374 patients with chronic plaque psoriasis who had been treated with methotrexate. Phenotypic data on efficacy and toxicity were available. Haplotype tagging SNPs (r(2)>0.8) across the relevant genes, with a minor allele frequency of >5%, were selected from the HAPMAP phase II data. SNPs within the efflux transporter genes ABCC1 (ATP-binding cassette, subfamily C, member 1) and ABCG2 (ATP-binding cassette, subfamily G, member 2) are associated with good response to methotrexate therapy in patients with psoriasis; the former gene was also associated with the onset of toxicity. With one SNP in ABCC1, rs246240, the carriage of two copies of allele 1 gives an odds ratio of 2.2 (95% confidence interval: 1.3-3.6; P=0.001) for developing toxicity to methotrexate. These data indicate that knowledge of SNPs in genes relevant to methotrexate efflux may be important in selecting patients suitable for this therapy.