Influence of Genetic Single Nucleotide Polymorphisms in CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1 Genes on Survival and Treatment Related Toxicity in Patients with Multiple Myeloma Treated in the HOVON 24 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 505-505 ◽  
Author(s):  
Pieter Sonneveld ◽  
Celine Schilthuizen ◽  
Henk Lokhorst ◽  
Edo Vellenga ◽  
Reinier Raymakers ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Single Nucleotide Polymorphisms ◽  
Enzymatic Activity ◽  
Drug Metabolizing Enzymes ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Free Survival ◽  
Intensified Chemotherapy

Abstract Cytochromes P450 (CYP 450) and gluthatione-S-transferases (GSTs) are drug metabolizing enzymes involved in the detoxification of numerous chemotherapeutic agents.The Multidrug Resistance gene 1 (MDR1, ABCB1) is a transmembrane drug transporter present in tumor cells and mucosal epithelium. Genetic single nucleotide polymorphisms (SNP’s) in these genes are frequent and may alter the metabolism of certain anti-cancer drugs. The CYP3A4*1B (A-290G) polymorphism has not yet been proven to alter enzymatic activity. Polymorphisms in the CYP3A5*3 gene (A6986G) and the GSTP1 gene (Ile105Val) lead to decreased enzymatic activity. Homozygous deletions in the GSTM1 and GSTT1 genes lead to complete absence of the enzyme. Genetic polymorphism of MDR1 (C3435T) are frequent and associated with enhanced efflux function. We hypothesized that SNP haplotypes of these drug metabolizing enzymes may determine the interindividual differences of patients to treatment response and toxicity. We have investigated the presence of SNP’s of 211/345 previously untreated patients with multiple myeloma from whom diagnostic material was available and who were treated according to the HOVON-24 protocol, a clinical trial comparing myeloablative therapy with stem cell rescue added to intensified chemotherapy to intensified chemotherapy alone. Peripheral blood or bone marrow samples were analyzed by PCR or multiplex PCR. Patients with different haplotypes of CYP3A4, GSTP1, GSTM1, GSTT1 genes did not have significant differences of overall survival (OS), time to progression (TTP), progression free survival (PFS), event free survival (EFS), partial remission (PR), complete remission (CR) as determined by multivariate analysis with all clinical variables. Patients with mutant GSTP1(Ile/Val) had significantly more toxicity following high-dose melphalan (p=0.003). Patients with MDR1 C3435T mutation or absence of GSTP1 Ile105Val mutations had a lower probability to achieve at least a partial response(p=0.01). Patients genotyped homozygously for the mutant allele CYP3A5 gene had increased toxicity (p=0.040), improved OS (p=0.01) and PFS (p=0.04) and a decrease in TTP (p=0.03). This study is part of an ongoing analysis and the results will be validated in the next HOVON trial. We conclude that in patients with multiple myeloma who are treated with intensive chemotherapy and stem cell transplantation, analysis of genetic polymorphisms of metabolic enzymes may improve our understanding of treatment associated toxicity and treatment outcome.

Impact of Single Nucleotide Polymorphisms in Genes Involved in DNA Repair and Drug Metabolism On Survival After Autologous Stem Cell Transplantation in Patients with Multiple Myeloma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2934-2934
Author(s):  
Carlos Fernández de Larrea ◽  
Alfons Navarro ◽  
Natalia Tovar ◽  
Fabiola Pedrosa ◽  
Tania Díaz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Repair ◽  
Stem Cell ◽  
Single Nucleotide Polymorphisms ◽  
Drug Metabolism ◽  
Stem Cell Transplantation ◽  
Genomic Dna ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Abstract Abstract 2934 Background: The analysis of polymorphisms in drug metabolism pathways and in DNA repair genes could help to identify patients with possible different treatment response and outcome. Single nucleotide polymorphisms (SNPs) are the most frequent type of genomic polymorphisms and have been described in association with prevalence, response to treatment, progression-free and overall survival in different tumors, including multiple myeloma (MM). The aim of the present study was to examine 22 SNPs related to DNA repair and drug metabolism, and correlate our findings with response, toxicity and survival in patients with MM after autologous stem-cell transplantation (ASCT). Patients and Methods: One hundred and eighty seven patients with MM (103M/84F, median age 55 years) intensified with melphalan-based ASCT have been studied in one institution. The median follow-up was 4 years (range 4 months to 18 years). None patient was lost to follow-up. Genomic DNA was isolated from bone marrow slides using a commercial assay (Qiagen). SNPs were analyzed by TaqMan assay in an ABI Prism 7500 Sequence Detection system (Applied Biosystems). The genes and SNPs evaluated in genomic DNA by allelic PCR were ERCC2 (rs13181, rs238406), ERCC5 (rs1047768, rs17655), XPA (rs1800975), XPC (rs2228001), XRCC1 (rs25487), XRCC5 (rs1051685, rs1051677), XRCC4 (rs963248), ERCC1 (rs3212948, rs735482) and BRCA1 (rs16941, rs799917) for DNA repair systems; NAT2 (rs1799930), CYP2C8 (rs11572080, rs2275622, rs10509681), TYMS (rs2790), SULT1 (rs1402467) and GST1 (rs1695) for phase I and II drug metabolisms, and ABCB1 (rs1045642) for drug transportation. These genes were selected based on their potential impact on prognosis in solid tumors in previous reports. Results: In the overall population, median PFS was 2.7 years (CI 95% 2.2 to 3.3 years), with a median OS of 6 years (CI 95% 4.5 to 8 years). OS was significantly shorter in patients with SNPs in ERCC5 (rs1047768; p=0.021), XPA (rs1800975; p=0.032) and GSTP1 (rs1695; p=0.015) (Figure). There was also a trend for CYP2C (rs2275622; p=0.054) and TYMS (p=0.107). The significance of the SNP in ERCC5 was retained in the group treated with conventional chemotherapy at induction (p=0.034), but not in those who received novel drugs (bortezomib, thalidomide and lenalidomide). Patients with SNP in ERCC1 achieved a lower CR rate (22.2% vs. 37.8%; p=0.033), with no prognostic significance. Polymorphism in GSTP1 was also associated with a shorter PFS (p=0.002), without differences in the complete remission (CR) rate. When only patients who received ASCT after first line treatment were considered, the effect over OS remained at significant level (p=0.039). Furthermore, the effect on PFS and OS was also significant in patients achieving CR after ASCT (p=0.03). NAT2 (rs1799930) and ERCC2 (rs238406) polymorphims were associated with clinically significant mucositis after conditioning, as well as TYMS (rs2790) with relevant gastrointestinal toxicity (p<0.02). No other associations with prognosis or toxicities were observed with the remaining SNPs. Conclusion: SNPs in differences DNA repair systems, such as ERCC5 and XPA, were associated with longer OS in patients MM after ASCT. Since these polymorphisms were not related to a better response or longer PFS, it can be speculated that the more prolonged OS could be due to a potential higher efficacy of rescue therapy. A SNP in GSTP1 (Ile105Val), a phase 2 drug metabolism enzyme involved in the metabolism and detoxification of a range of chemotherapeutic agents including melphalan, was associated with a shorter PFS and OS, as reported in previous series. Our findings could be useful to identify patients with MM who are more likely to benefit from melphalan-based therapies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The role of functional polymorphisms in oxidative stress-related genes on early-stage breast cancer survival

2021 ◽  
pp. 172460082110111
Author(s):  
Erika Korobeinikova ◽  
Rasa Ugenskiene ◽  
Ruta Insodaite ◽  
Viktoras Rudzianskas ◽  
Jurgita Gudaitiene ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Single Nucleotide Polymorphisms ◽  
Early Stage ◽  
Disease Free Survival ◽  
Early Stage Breast Cancer ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Free Survival ◽  
Disease Free

Background: Genetic variations in oxidative stress-related genes may alter the coded protein level and impact the pathogenesis of breast cancer. Methods: The current study investigated the associations of functional single nucleotide polymorphisms in the NFE2L2, HMOX1, P21, TXNRD2, and ATF3 genes with the early-stage breast cancer clinicopathological characteristics and disease-free survival, metastasis-free survival, and overall survival. A total of 202 Eastern European (Lithuanian) women with primary I–II stage breast cancer were involved. Genotyping of the single nucleotide polymorphisms was performed using TaqMan single nucleotide polymorphisms genotyping assays. Results: The CA+AA genotypes of P21 rs1801270 were significantly less frequent in patients with lymph node metastasis and larger tumor size ( P=0.041 and P=0.022, respectively). The TT genotype in ATF3 rs3125289 had significantly lower risk of estrogen receptor (ER), progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) positive status ( P=0.023, P=0.046, and P=0.040, respectively). In both, univariate and multivariate Cox analysis, TXNRD2 rs1139793 GG genotype vs. GA+AA was a negative prognostic factor for disease-free survival (multivariate hazard ratio (HR) 2.248; P=0.025) and overall survival (multivariate HR 2.248; P=0.029). The ATF3 rs11119982 CC genotype in the genotype model was a negative prognostic factor for disease-free survival (multivariate HR 5.878; P=0.006), metastasis-free survival (multivariate HR 4.759; P=0.018), and overall survival (multivariate HR 3.280; P=0.048). Conclusion: Our findings suggest that P21 rs1801270 is associated with lymph node metastasis and larger tumor size, and ATF3 rs3125289 is associated with ER, PR, and HER2 status. Two potential, novel, early-stage breast cancer survival biomarkers, TXNRD2 rs1139793 and ATF3 rs11119982, were detected. Further investigations are needed to confirm the results of the current study.

Impact on response and survival of DNA repair single nucleotide polymorphisms in relapsed or refractory multiple myeloma patients treated with thalidomide

2011 ◽  
Vol 35 (9) ◽  
pp. 1178-1183 ◽  
Author(s):  
María Teresa Cibeira ◽  
Carlos Fernández de Larrea ◽  
Alfons Navarro ◽  
Tania Díaz ◽  
Dolors Fuster ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Repair ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Refractory Multiple Myeloma

Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2650-2657 ◽  
Author(s):  
Hervé Ghesquières ◽  
Guillaume Cartron ◽  
John Francis Seymour ◽  
Marie-Hélène Delfau-Larue ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Follicular Lymphoma ◽  
Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Free Survival ◽  
Rituximab Maintenance

Abstract In patients with follicular lymphoma treated with single-agent rituximab, single nucleotide polymorphisms in the FCGR3A gene are known to influence response and progression-free survival. The prognostic role of FCGR3A and FCGR2A polymorphisms in patients with follicular lymphoma treated with rituximab and chemotherapy combination remains controversial and has not been evaluated in the context of rituximab maintenance. FCGR3A and FCGR2A single nucleotide polymorphisms were evaluated in, respectively, 460 and 455 patients treated in the PRIMA study to investigate whether these were associated with response rate and patient outcome after rituximab chemotherapy induction and 2-year rituximab maintenance. In this representative patient cohort, complete and unconfirmed complete responses after rituximab chemotherapy were observed in 65%, 67%, 66% (P = .86) and 60%, 72%, 66% (P = .21) of FCGR3A VV, VF, FF and FCGR2A HH, HR, RR carriers, respectively. After 2 years of rituximab maintenance (or observation), response rates did not differ among the different genotypes. Progression-free survival measured from either treatment initiation or randomization to observation or maintenance was not influenced by these polymorphisms. These data indicate that FCGR3A and FCGR2A polymorphisms do not influence response rate and outcome when rituximab is combined with chemotherapy or used as maintenance treatment. The PRIMA study is registered at www.clinicaltrials.gov as NCT00140582.

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