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Cerón Maldonado R, Martínez Tovar A, Ramos Peñafiel CO, De la Cruz Rosas A, García Laguna AI, Mendoza Salas I, Martínez Murillo C, Barranco Lampón GI, Montaño Figueroa EH, Jiménez-Morales S, Olarte Carrillo I. CYP3A5 Polymorphism in Circulating Tumor Cells Confers an Increased Disease-Free Survival in DLBCL Patients Treated with R-CHOP. Onco Targets Ther 2025; 18:355-366. [PMID: 40109410 PMCID: PMC11920637 DOI: 10.2147/ott.s486400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 03/04/2025] [Indexed: 03/22/2025] Open
Abstract
Purpose Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous aggressive lymphoid neoplasm. Cases of refractoriness and relapse persist in approximately 40% of patients treated with first-line R-CHOP regimen, thus, the identification of factors associated with disease progression have become a necessity. Diverse polymorphisms in genes encoding proteins involved in the metabolism and elimination of chemotherapeutic drugs have been studied as potential causes of treatment failure. In oncology, liquid biopsies have emerged as a non-invasive method for detecting circulating biomarkers, thereby strengthening both diagnosis and prognosis for patients. Therefore, the purpose of this study was to determine polymorphisms in Circulating Tumor Cells (CTCs) to describe the relevance of liquid biopsy in the clinical outcomes of patients with DLBCL. Patients and Methods We analyzed 102 liquid biopsies of peripheral blood from DLBCL patients, of which CTCs were isolated by density gradient and CD20 immunomagnetic antibodies. Allelic discrimination assays were performed to analyze ABCB1 C3435T, ABCG2 C421A and CYP3A5 A6986G polymorphisms. Overall survival (OS) and disease-free survival (DFS) analysis were performed using Kaplan-Meier curves and risk analysis was performed using Cox regression. Results We found that GG genotype of CYP3A5 A6986G was associated with a longer DFS (68.6% vs 49%, p=0.019) and lower risk of course with adverse event related to disease (progression, relapse and death) (OR 0.374, CI 0.187-0.745, p=0.011). No significant associations were found between ABCB1 C3435T and ABCG2 C421A genotype with the clinical outcome. Conclusion In this study, we demonstrated that in CTCs derived from liquid biopsies, the GG genotype in the CYP3A5 A6986G, which is related to the metabolism and elimination of chemotherapy drugs, impacts in longer DFS. These findings confirm the relevance of circulating biomarkers in non-invasive biological samples for strengthening the prognosis of DLBCL.
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Affiliation(s)
- Rafael Cerón Maldonado
- Posgrado en Ciencias Biológicas, Biomedicina, UNAM, CDMX, México
- Department of Investigation, Hematology Service, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Adolfo Martínez Tovar
- Department of Investigation, Hematology Service, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico
| | | | - Adrián De la Cruz Rosas
- Department of Investigation, Hematology Service, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Anel Irais García Laguna
- Department of Investigation, Hematology Service, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Iveth Mendoza Salas
- Department of Investigation, Hematology Service, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Carlos Martínez Murillo
- Department of Medical Hematology, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico
| | | | | | - Silvia Jiménez-Morales
- Laboratorio de Innovación y Medicina de Precisión, Núcleo "A", Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Irma Olarte Carrillo
- Posgrado en Ciencias Biológicas, Biomedicina, UNAM, CDMX, México
- Department of Investigation, Hematology Service, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico
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Spector SA, Brummel SS, Chang A, Wiznia A, Ruel TD, Acosta EP. Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children. J Acquir Immune Defic Syndr 2024; 95:297-303. [PMID: 38180896 PMCID: PMC10922521 DOI: 10.1097/qai.0000000000003358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 08/22/2023] [Indexed: 01/07/2024]
Abstract
BACKGROUND Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined. METHODS Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. RESULTS The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 ; 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts. CONCLUSIONS Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.
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Affiliation(s)
- Stephen A. Spector
- University of California San Diego, La Jolla, CA and Rady Children’s Hospital San Diego, San Diego, CA
| | - Sean S. Brummel
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health
| | - Audrey Chang
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health
| | - Andrew Wiznia
- Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY
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Association of ABCB1, ABCG2 drug transporter polymorphisms and smoking with disease risk and cytogenetic response to imatinib in chronic myeloid leukemia patients. Leuk Res 2023; 126:107021. [PMID: 36696828 DOI: 10.1016/j.leukres.2023.107021] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
BACKGROUND Despite acceptable results of imatinib in the treatment of chronic myeloid leukemia (CML), some patients fail to acquire a complete cytogenetic response (CCyR), which may be caused by polymorphisms in the pharmacogenetic genes. The study aimed to evaluate the association of two polymorphisms in the ABCB1 and ABCG2 genes with cytogenetic response to imatinib and the risk of CML development. METHODS We genotyped ABCB1 (c .2677G/T/A) and ABCG2 (c .421C/A) polymorphisms by PCR-RFLP, T-ARMS-PCR methods in 111 patients with CML and 102 sex- and age-matched healthy subjects. CCyR was determined by standard chromosome banding analysis (CBA). RESULTS Analysis of polymorphisms showed significant association of ABCG2 c.421CA genotype (p < 0.0001; OR = 0. 17), and ABCG2c.421A allele (p < 0.0001; OR = 0.31) with decreased risk of CML. Moreover, ABCB1c.2677GT- ABCG2c.421CC combined genotype (p = 0.017; OR = 4.20) was associated with increased risk of CML. Analysis of the joint effect of SNP-smoking combination showed that smoker subjects with the ABCB1c.2677GG/GT (p = 0.001; OR = 15.96, p = 0.001; OR = 8.13, respectively) or ABCG2c.421CC genotypes (p = 0.001; OR = 5.82) had the increased risk of CML, while the risk of the CML in non-smokers carrying the ABCG2c.421CA (p < 0.0001; OR = 0. 18) genotype was strongly decreased compared with reference group. Regarding drug response, ABCG2c.421 CC/CA genotypes in the smoker patients were associated with an increased risk of resistance to imatinib (p < 0.0001; OR = 7.02, p = 0.018; OR = 4.67, respectively). CONCLUSION Our results suggest the impact of ABCG2c .421C/A polymorphism on CML development, and smoking may have a synergistic role in the risk of CML and resistance to imatinib.
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Nouri N, Mehrzad V, Khalaj Z, Zaker E, Zare F, Abbasi E, Khosravi M, Kalantar SM, Salehi M. Effects of ABCG2 C421A and ABCG2 G34A genetic polymorphisms on clinical outcome and response to imatinib mesylate, in Iranian chronic myeloid leukemia patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2023. [DOI: 10.1186/s43042-022-00379-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Abstract
Background
Chronic myeloid leukemia (CML) is a multifactorial clonal myeloid neoplasm that mainly arises from the Philadelphia chromosome. Even though imatinib mesylate (IM) is considered the gold standard for first-line treatment, a number of CML patients have shown IM resistance that can be influenced by many factors, including pharmacogenetic variability. The present study examined whether two common single nucleotide polymorphisms (SNPs) of ABCG2 (G34A and C421A) contribute to IM resistance and/or good responses.
Material and methods
A total of 72 CML patients were genotyped with high-resolution melting (HRM) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). We also determined the cytogenetic and hematological response, as evaluable factors for measuring response to imatinib.
Results
In the current study, we explored the relationship between the different variants of ABCG2 G34A and C421A and clinical response to imatinib among CML patients. There were no statistically significant differences between genotypes of C421A and G34A and allele frequencies among the resistant and responder groups, with response to IM (P > 0.05). Also, we found no statistically significant association between genotypes and cytogenetic and hematological responses.
Conclusion
This is the first study to investigate the association between genotypes of the G34A and C421A SNPs and the outcome of IM treatment in Iranian population. As a whole, genotyping of these SNPs is unhelpful in predicting IM response in CML patients.
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Genetic Variants of ABC and SLC Transporter Genes and Chronic Myeloid Leukaemia: Impact on Susceptibility and Prognosis. Int J Mol Sci 2022; 23:ijms23179815. [PMID: 36077209 PMCID: PMC9456284 DOI: 10.3390/ijms23179815] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/27/2022] Open
Abstract
Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants—SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters’ SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.
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Viana Filho JMC, Coêlho MDC, Ribeiro ILA, Persuhn DC, Valença AMG, Oliveira NFPD. ABCG2 polymorphism, age and leukocyte count may contribute to oral mucositis in oncopediatric patients. Braz Dent J 2021; 32:14-26. [PMID: 34614057 DOI: 10.1590/0103-6440202103768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 02/15/2021] [Indexed: 11/21/2022] Open
Abstract
The study investigated the relationship between genetic polymorphisms and the development of oral mucositis in pediatric patients undergoing chemotherapy involving methotrexate. A longitudinal study was conducted with 64 patients, and oral mucositis was evaluated by the modified Oral Assessment Guide, which aims to diagnose and classify oral mucositis. Epithelial cells were obtained by mouthwash and DNA was extracted. The polymorphisms MTHFR (rs1801133), DNMT3B (rs2424913), ABCC2 (rs717620), ABCG2 (rs2231137) and ABCG2 (rs2231142) were analyzed by PCR-RFLP method. Demographic, hematological and biochemical data were collected from medical records. Statistical analysis was performed using the SPSS software adopting a p-value of 0.05. Male sex predominated (56.2%), and the mean age was 10.8 years (± 4.9). Oral mucositis affected 65.6% of the patients, of which 61.9% developed the severe form of the disease. For the ABCG2 gene (rs2231142), the rare A allele and CA genotype were more frequent in individuals with mucositis (p= 0.02; RR = 0.60; CI = 0.387 - 0.813). The severity of the disease was mainly observed in younger patients (median = 9 years; p=0.02). Patients with severe oral mucositis presented lower leukocytes count (median = 2.150 mm3) compared to patients with the mild/moderate form (median = 4.200 mm3; p=0.03). Female patients and each 10,000-platelet increase were protective factors against the onset of oral mucositis (p=0.02). It is concluded that rs2231142 polymorphism increases the likelihood of oral mucositis and younger patients and patients with low leukocytes counts are more likely to develop severe form.
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Affiliation(s)
- José Maria Chagas Viana Filho
- Graduate Program in Dentistry, Health Sciences Center, Federal University of Paraiba (Universidade Federal da Paraíba- UFPB), João Pessoa, Paraíba (PB), Brazil
| | - Marina de Castro Coêlho
- Graduate Program in Dentistry, Health Sciences Center, Federal University of Paraiba (Universidade Federal da Paraíba- UFPB), João Pessoa, Paraíba (PB), Brazil
| | | | - Darlene Camati Persuhn
- Department of Molecular Biology, Center for Exact and Natural Sciences, UFPB, João Pessoa, PB, Brazil
| | - Ana Maria Gondim Valença
- Graduate Program in Dentistry, Health Sciences Center, Federal University of Paraiba (Universidade Federal da Paraíba- UFPB), João Pessoa, Paraíba (PB), Brazil.,Department of Statistics, Center for Exact and Natural Sciences, UFPB, João Pessoa, PB, Brazil
| | - Naila Francis Paulo de Oliveira
- Graduate Program in Dentistry, Health Sciences Center, Federal University of Paraiba (Universidade Federal da Paraíba- UFPB), João Pessoa, Paraíba (PB), Brazil.,Department of Molecular Biology, Center for Exact and Natural Sciences, UFPB, João Pessoa, PB, Brazil
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Amouei A, Daeian N, Khezrnia SS, Mansouri A, Hadjibabaie M. Imatinib Efficacy, Safety and Resistance in Iranian Patients with Chronic Myeloid Leukemia: A Review of Literature. Int J Hematol Oncol Stem Cell Res 2021; 15:114-131. [PMID: 34466210 PMCID: PMC8381106 DOI: 10.18502/ijhoscr.v15i2.6042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 05/17/2020] [Indexed: 11/24/2022] Open
Abstract
Background: Imatinib is the gold standard in the treatment of chronic myeloid leukemia (CML) patients. Resistance to imatinib is interfering with patients’ responses and their survivals. Materials and Methods: We designed a systematic search to find relevant studies by applying appropriate keywords in PubMed, Web of science, Scopus, Ovid, ProQuest, Science direct and Google scholar for English studies. We also investigated the aforementioned terms’ correspondence in Magiran, Scientific information database (SID) and Google scholar for Persian articles. Results: 25 studies were selected for final analysis. Reported hematologic responses from adult studies ranged 86-99% and major molecular responses were estimated in 38.84% of our patients within 12 months of treatment. The most frequent reported adverse drug reactions (ADRs) were edema (n=5 studies, 100%) and fatigue and nausea (n=4 studies, 80%); ADR per capita ratio was 1.46. Only one study informed ADRs in pediatrics demonstrating 93% of patients experienced ADRs after receiving imatinib. Most of the Studies (n=4, 67% from 7 studies) considered BCR/ABL point mutation as main reason of imatinib resistance. Drug-binding site and P-loop regions were two common sites for BCR/ABL point mutation. Conclusion: Imatinib as the first line treatment for CML has been associated with proper and durable responses in Iranian adults and children CML patients. Moreover, Imatinib life-threatening adverse effects were reported uncommon. Various responses to modified regimens have been reported in resistant patients; therefore, individualized treatment based on mutation type could be recommended.
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Affiliation(s)
- Asiyeh Amouei
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
| | - Nesa Daeian
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh Sana Khezrnia
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
| | - Ava Mansouri
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
| | - Molouk Hadjibabaie
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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DNA Repair Genes and Chronic Myeloid Leukemia: ERCC2 (751), XRCC1 (399), XRCC4-Intron 3, XRCC4 (-1394) Gene Polymorphisms. Mediterr J Hematol Infect Dis 2021; 13:e2021020. [PMID: 33747401 PMCID: PMC7938920 DOI: 10.4084/mjhid.2021.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 02/12/2021] [Indexed: 12/31/2022] Open
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Louati N, Turki F, Mnif H, Frikha R. MDR1 gene polymorphisms and imatinib response in chronic myeloid leukemia: A meta-analysis. J Oncol Pharm Pract 2021; 28:39-48. [PMID: 33565361 DOI: 10.1177/1078155220981150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Our study aimed to investigate the association between multidrug resistance (MDR1) C1236T, C3435T and G2677T/A polymorphisms and the response to imatinib (IM) in chronic myeloid leukemia (CML). MATERIALS AND METHODS An electronic databases in PubMed, Embase, Web of Knowledge, Scopus and Cochrane were searched using combinations of keywords relating to MDR1 polymorphisms and the response to IM in CML. Studies retrieved from database searches were screened using strict inclusion and exclusion criteria. RESULTS In total, 37 studies were initially identified, and 17 studies, involving 4494 CML patients, were eventually included in this meta-analysis.Results of our study revealed significant association between MDR1 G2677T/A and C3435T polymorphisms and response to IM in Caucasian population under recessive model (T or A vs G; OR = 1.43,95%CI [1;06-1.93]; T vs C;OR = 1.13; 95%IC [0.79; 1.63]), dominant (T or A vs G; OR = 0.94; 95%CI [0.74-1.21]; T vs C; OR = 1.49; 95%CI [1.02-2.17]) and heterozygous models (T or A vs G; OR = 0.83; 95%CI [0.64; 1.09]; T vs C; OR = 1.52; 95%CI [1.01-2.28]); respectively. However, never significative association was found between IM response and the MDR1 C1236T polymorphism (OR = 1.25; 95%CI [0.46; 3.33]). CONCLUSION The MDR1 G2677T/A and C3435T polymorphisms might be a risk factor for resistance to IM in Caucasian CML patients.
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Affiliation(s)
- N Louati
- Blood Bank, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
| | - F Turki
- Department of Medical Genetic, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
| | - H Mnif
- Blood Bank, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
| | - R Frikha
- Department of Medical Genetic, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
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Rahimian E, Amini A, Alikarami F, Pezeshki SMS, Saki N, Safa M. DNA repair pathways as guardians of the genome: Therapeutic potential and possible prognostic role in hematologic neoplasms. DNA Repair (Amst) 2020; 96:102951. [PMID: 32971475 DOI: 10.1016/j.dnarep.2020.102951] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 07/30/2020] [Accepted: 08/10/2020] [Indexed: 11/30/2022]
Abstract
DNA repair pathways, which are also identified as guardians of the genome, protect cells from frequent damage that can lead to DNA breaks. The most deleterious types of damage are double-strand breaks (DSBs), which are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). Single strand breaks (SSBs) can be corrected through base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Failure to restore DNA lesions or inappropriately repaired DNA damage culminates in genomic instability and changes in the regulation of cellular functions. Intriguingly, particular mutations and translocations are accompanied by special types of leukemia. Besides, expression patterns of certain repair genes are altered in different hematologic malignancies. Moreover, analysis of mutations in key mediators of DNA damage repair (DDR) pathways, as well as investigation of their expression and function, may provide us with emerging biomarkers of response/resistance to treatment. Therefore, defective DDR pathways can offer a rational starting point for developing DNA repair-targeted drugs. In this review, we address genetic alterations and gene/protein expression changes, as well as provide an overview of DNA repair pathways.
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Affiliation(s)
- Elahe Rahimian
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Amini
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Alikarami
- Center for Childhood Cancer Research, Children's Hospital of Philadelphia (CHOP), Philadelphia, PA 19104, USA
| | - Seyed Mohammad Sadegh Pezeshki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Pena MÁ, Muriel J, Saiz-Rodríguez M, Borobia AM, Abad-Santos F, Frías J, Peiró AM. Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects. Clin Drug Investig 2020; 40:617-628. [PMID: 32415468 DOI: 10.1007/s40261-020-00921-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles. OBJECTIVE To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters. METHODS A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software. RESULTS Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity. CONCLUSION CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib.
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Affiliation(s)
- María Ángeles Pena
- Alicante Clinical Trials Unit, Department of Health, Alicante-General Hospital, Alicante, Spain.,Clinical Pharmacology Service, Department of Health, Alicante-General Hospital, c/Pintor Baeza, 12, 03010, Alicante, Spain
| | - Javier Muriel
- Alicante Institute for Health and Biomedical Research (ISABIAL Foundation), Alicante, Spain
| | - Miriam Saiz-Rodríguez
- Clinical Pharmacology Service, University Hospital La Princesa, Autonomous University of Madrid, Madrid, Spain
| | - Alberto M Borobia
- Clinical Pharmacology Department, La Paz University Hospital, Universidad Autónoma de Madrid. IdiPAZ, Madrid, Spain
| | - Francisco Abad-Santos
- Clinical Pharmacology Service, University Hospital La Princesa, Autonomous University of Madrid, Madrid, Spain.,Institute Teófilo Hernando for Drug I+D, School of Medicine, Autonomous University of Madrid, Madrid, Spain
| | - Jesús Frías
- Clinical Pharmacology Department, La Paz University Hospital, Universidad Autónoma de Madrid. IdiPAZ, Madrid, Spain
| | - Ana M Peiró
- Alicante Clinical Trials Unit, Department of Health, Alicante-General Hospital, Alicante, Spain. .,Clinical Pharmacology Service, Department of Health, Alicante-General Hospital, c/Pintor Baeza, 12, 03010, Alicante, Spain.
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Omran MM, Abdelfattah R, Moussa HS, Alieldin N, Shouman SA. Association of the Trough, Peak/Trough Ratio of Imatinib, Pyridine-N-Oxide Imatinib and ABCG2 SNPs 34 G>A and SLCO1B3 334 T>G With Imatinib Response in Egyptian Chronic Myeloid Leukemia Patients. Front Oncol 2020; 10:1348. [PMID: 32974132 PMCID: PMC7466443 DOI: 10.3389/fonc.2020.01348] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
Imatinib mesylate (IM) is highly efficacious in the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to gain a greater mechanistic understanding of the factors controlling variability in IM level and its relation to the response. One hundred and two patients with CML at chronic phase were recruited in this study. Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were determined by HPLC/MS/MS. Genetic polymorphism of the genes ABCG2 SNPs 34 G>A and 421C >A; ABCB1 SNPs 2677 G>A/T, 1236 C>T, 3435 C>T; SLCO1B3 SNPs 334 T>G and CYP3A5 were studied using PCR-RFLP technique. Our study presented significant higher trough IM (1,281 ± 578 ng/ml), lower Peak/Trough ratio, clearance (Cl), and elimination rate constant, ke, among patients who achieved favorable responses (N = 64) than those for patients who suffered unfavorable response (N = 37). The P/T ratio was the only significant independent factor affecting response, as the P/T ratio increased by one, the risk of unfavorable response increased by more than double as compared to favorable response with 95% CI (1.28-3.92, P = 00.005). Moreover, like the results of IM, the trough concentration of Pyridine-N-oxide imatinib was significantly higher (P = 0.01) and its P/T ratio was significantly lower (P = 0.008) in patients achieved favorable response than those without. The wild GG genotype of the ABCG2.34 G>A gene was associated with favorable response (P = 0.01), lower Cl, Ke and high plasma IM trough level than both (AA+GA) genotypes. ABCG2.421C >A (CC) genotype had a significantly higher plasma peak of IM, N-des-methyl imatinib and higher Css. The GG and TG alleles of the SLCO1B3.334 T>G gene were significantly correlated to favorable response, while the wild allele TT was linked to unfavorable response (P = 0.03). In conclusion, the trough and P/ T ratio for both IM and Pyridine-N-oxide imatinib, in addition to Polymorphism of ABCG2 SNPs 34 G>A and SLCO1B3.334 T>G gene, is a good predictor for response of IM in CML Egyptian patients.
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Affiliation(s)
- Mervat M Omran
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Raafat Abdelfattah
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Heba S Moussa
- Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Nelly Alieldin
- Medical Statistics Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Samia A Shouman
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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13
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Cai W, Liu X, Li Y, Bi B, Liu L, Wang Z. New sights on the associations between the XRCC1 gene polymorphisms and hepatocellular carcinoma susceptibility. J Cell Biochem 2019; 121:1005-1022. [PMID: 31478224 DOI: 10.1002/jcb.29335] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 07/15/2019] [Indexed: 01/27/2023]
Affiliation(s)
- Wenjuan Cai
- Department of Pathology Tianjin First Centre Hospital Tianjin China
| | - Xinhua Liu
- School of Biomedical Engineering Tianjin Medical University Tianjin China
| | - Yan Li
- Biological Sample Resource Sharing Center Tianjin First Centre Hospital Tianjin China
| | - Bowen Bi
- Biological Sample Resource Sharing Center Tianjin First Centre Hospital Tianjin China
| | - Lei Liu
- Department of Transplantation Tianjin First Centre Hospital Tianjin China
- Key Laboratory of Transplantation Chinese Academy of Medical Sciences Beijing China
| | - Zhenglu Wang
- Department of Pathology Tianjin First Centre Hospital Tianjin China
- Tianjin Key Laboratory for Organ Transplantation Tianjin China
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14
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Lack of association between functional polymorphism of DNA repair genes (XRCC1, XPD) and clinical response in Indian chronic myeloid leukemia patients. Mol Biol Rep 2019; 46:4997-5003. [PMID: 31286393 DOI: 10.1007/s11033-019-04950-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 06/27/2019] [Indexed: 02/07/2023]
Abstract
The resistance for the tyrosine kinase inhibitors in chronic myeloid leukemia (CML) occurs mainly due to BCR/ABL1 dependent and independent mechanisms. The defective DNA repair due to functional polymorphisms in DNA repair genes, might act as an etiological factor for leukemia progression. The study was carried out to understand the role of DNA repair genes (XRCC1, XPD) polymorphisms in Imatinib mesylate (IM) resistant CML patients. The study was carried out in total 87 CML patients (43 nonresponders-cases and 44 responders) who were treated with Imatinib. The treatment and follow-up was done according to European LeukemiaNet guidelines. The genotyping of selected SNPs were studied using RFLP and confirmed with Sanger sequencing (20%). The statistical analysis was performed using online tools (Socscistatistics and GraphPad InStat software). In our study no significant association was inferred between genotypes of DNA repair genes (XRCC1; rs1799782, rs25487, and XPD; rs13181) and complete cytogenetic response as well as molecular response. However there might be a possibility of association between XRCC1 Arg399Gln genotype AA/GA and cytogenetic response though it is statistically insignificant (p > 0.05). Though none of the genotypes of the DNA repair genes showed association with IM response, near association between XRCC1Arg399Gln genotype and cytogenetic response observed in our study. Hence, large sample size should be studied to establish the association of SNPs of DNA repair genes and IM response. Our study is a novel and important to explain the role of DNA repair genes polymorphisms in IM resistance.
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15
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Maués T, El-Jaick KB, Costa FB, Freitas PVS, Moreira AS, Castro L, Ferreira MLG, Ferreira AMR. Could polymorphisms in ABCB1 gene represent a genetic risk factor for the development of mammary tumors in dogs? Vet J 2019; 248:58-63. [PMID: 31113564 DOI: 10.1016/j.tvjl.2019.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 04/18/2019] [Accepted: 04/18/2019] [Indexed: 01/09/2023]
Abstract
The ABCB1 gene encodes the P-glycoprotein (P-gp) which regulates distribution and bioavailability of many endogenous and exogenous substrates, acting as a cellular mechanism of protection against these substances. Some studies have shown evidence that P-gp is related to carcinogenesis. In this study, we performed PCR and direct sequencing of ABCB1 exons 9 and 26 in 47 tissue DNA samples from canine mammary tumors. A statistically significant correlation between distinct canine breeds and the frequency of ABCB1 polymorphisms (c.985T > A and c.3442A > G SNP in ABCB1exons 9 and 26, respectively) was observed (P = 0.0015). In contrast, the TNM clinical staging, age, histological type and grade, as well as other histopathological characteristics, did not present statistically significant difference in relation to one or both SNP found in exons 9 and 26. These findings raise questions about the role of the canine ABCB1 polymorphisms in the development of mammary tumors, since the Poodle breed, which is the most common dog breed affected by mammary tumors in Brazil, presented the highest frequency of these variants. Notwithstanding, additional studies comprising a number of samples expressing the ABCB1 gene from healthy dogs, with advanced age and from different breeds, will be necessary to confirm the association of ABCB1polymorphisms and the development of mammary tumors.
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Affiliation(s)
- T Maués
- Department of Pathology and Veterinary Clinic, Faculty of Veterinary, UFF, Av. Alm. Ary Parreiras, 507, Icaraí, 24220-000, Niterói, RJ, Brazil.
| | - K B El-Jaick
- Department of Genetics and Molecular Biology, UNIRIO, R. Frei Caneca, 94, Centro, 20211-010, Rio de Janeiro, RJ, Brazil
| | - F B Costa
- Department of Animal Pathology, Veterinary School, UFMG, Av. Antônio Carlos, 6627, Sala 312, Pampulha, 31270-901, Belo Horizonte, MG, Brazil
| | - P V S Freitas
- Department of Genetics and Molecular Biology, UNIRIO, R. Frei Caneca, 94, Centro, 20211-010, Rio de Janeiro, RJ, Brazil
| | - A S Moreira
- Laboratory of Functional Genomics and Bioinformatics, RPT01A DNA Sequencing Platforms, Fiocruz, Av. Brasil, 4365, Manguinhos, 21040-360, Rio de Janeiro, RJ, Brazil
| | - L Castro
- National Institute of Infectology, Pharmacogenetics Research Laboratory, Fiocruz, Av. Brasil, 4365, Manguinhos, 21040-360, Rio de Janeiro, RJ, Brazil
| | - M L G Ferreira
- Department of Pathology and Veterinary Clinic, Faculty of Veterinary, UFF, Av. Alm. Ary Parreiras, 507, Icaraí, 24220-000, Niterói, RJ, Brazil
| | - A M R Ferreira
- Department of Pathology and Veterinary Clinic, Faculty of Veterinary, UFF, Av. Alm. Ary Parreiras, 507, Icaraí, 24220-000, Niterói, RJ, Brazil
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16
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Abstract
The transport of specific molecules across lipid membranes is an essential function of all living organisms. The processes are usually mediated by specific transporters. One of the largest transporter families is the ATP-binding cassette (ABC) family. More than 40 ABC transporters have been identified in human, which are divided into 7 subfamilies (ABCA to ABCG) based on their gene structure, amino acid sequence, domain organization, and phylogenetic analysis. Of them, at least 11 ABC transporters including P-glycoprotein (P-GP/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2) are involved in multidrug resistance (MDR) development. These ABC transporters are expressed in various tissues such as the liver, intestine, kidney, and brain, playing important roles in absorption, distribution, and excretion of drugs. Some ABC transporters are also involved in diverse cellular processes such as maintenance of osmotic homeostasis, antigen processing, cell division, immunity, cholesterol, and lipid trafficking. Several human diseases such as cystic fibrosis, sitosterolemia, Tangier disease, intrahepatic cholestasis, and retinal degeneration are associated with mutations in corresponding transporters. This chapter will describe function and expression of several ABC transporters (such as P-GP, BCRP, and MRPs), their substrates and inhibitors, as well as their clinical significance.
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Affiliation(s)
- Xiaodong Liu
- China Pharmaceutical University, Nanjing, China.
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17
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Belohlavkova P, Vrbacky F, Voglova J, Racil Z, Zackova D, Hrochova K, Malakova J, Mayer J, Zak P. The significance of enzyme and transporter polymorphisms for imatinib plasma levels and achieving an optimal response in chronic myeloid leukemia patients. Arch Med Sci 2018; 14:1416-1423. [PMID: 30393497 PMCID: PMC6209720 DOI: 10.5114/aoms.2018.73538] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/16/2017] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Imatinib mesylate is the drug of choice for patients with chronic myeloid leukemia (CML). Imatinib pharmacokinetics is affected by a number of transport proteins and enzymes. MATERIAL AND METHODS In the present study we evaluated the association of eight polymorphisms in the seven genes CYP3A5*3 (rs776746), CYP3A4*1 (rs2740574), CYP2C9*3 (rs1057910), SLC22A1 (rs683369), ABCB1 (rs1045642, rs1128503), ABCG2 (rs2231142) and ABCC2 (rs717620) with imatinib plasma level and achieving an optimal clinical response in 112 CML patients (53 men and 59 women). RESULTS No association was found between the examined polymorphisms in rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 and the achieved imatinib plasma level. The influence of rs776746 (CYP3A5*3) on the achievement of a complete cytogenetic response (CCyR) at 6 months was borderline non-significant (p = 0.06). Furthermore, no association was demonstrated between rs776746 polymorphisms and the achievement of a major molecular response (MMR) at 12 or 18 months. Polymorphisms rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 showed no impact on the optimal therapeutic response. CONCLUSIONS Despite the results of some other studies, no other polymorphism we analyzed was associated with imatinib plasma level or clinical response. The treatment outcomes cannot be predicted using the candidate gene approach and treatment decisions cannot be made according to the polymorphisms investigated in this study.
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Affiliation(s)
- Petra Belohlavkova
- 4 Department of Internal Medicine – Hematology, Charles University Hospital, Hradec Kralove, Czech Republic
| | - Filip Vrbacky
- 4 Department of Internal Medicine and Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic
| | - Jaroslava Voglova
- 4 Department of Internal Medicine and Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic
| | - Zdenek Racil
- Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic
| | - Daniela Zackova
- Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic
| | - Katerina Hrochova
- Department of Clinical Biochemistry, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic
| | - Jana Malakova
- Department of Clinical Biochemistry, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic
| | - Jiri Mayer
- Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic
| | - Pavel Zak
- 4 Department of Internal Medicine and Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic
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18
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Polymorphisms of ABCG2 and its impact on clinical relevance. Biochem Biophys Res Commun 2018; 503:408-413. [PMID: 29964015 DOI: 10.1016/j.bbrc.2018.06.157] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 12/11/2022]
Abstract
Human ABCG2 is one of the most important ATP-binding cassette (ABC) transporters. This protein functions as a xenobiotic transporter of large, hydrophobic, positively or negatively charged molecules, a wide variety anticancer drugs, fluorescent dyes, and different toxic compounds found in normal food. SNPs in ABCG2 may affect absorption and distribution of these substrates, altering the accumulation, effectiveness and toxicity of compounds or drugs in large populations. Its transport properties have been implicated clinically and ABCG2 expression is linked with different disease states. We reviewed the SNPs of ABCG2 in clinical relevance about gout, acute myeloid leukemia, solid tumors, and other diseases.
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19
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Zarei F, Menbari MN, Ghaderi B, Abdi M, Vahabzadeh Z. Higher risk of progressing breast cancer in Kurdish population associated to CDH1 -160 C/A polymorphism. EXCLI JOURNAL 2017; 16:1198-1205. [PMID: 29285016 PMCID: PMC5736986 DOI: 10.17179/excli2017-843] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 10/19/2017] [Indexed: 12/26/2022]
Abstract
There is an increasing interest about studying possible effects of genetic polymorphisms and risk of cancer progression. E-cadherin (CDH1) involves in many important cellular processes including cell-cell interactions, cell development and genetic changes of this molecule has been associated with greater tumor metastasis. The present study was aimed to evaluate the possible role of CDH1 -160 C/A polymorphism as a potential risk factor for breast cancer in Kurdish population. This case-control study consisted of 100 breast cancer patients and 200 healthy controls. Clinicopathological findings of all individuals were reported and immunohistochemistry staining was carried out on tissue samples. The CDH1 -160 C/A genotype was determined by polymerase chain reaction- restriction fragment length polymorphism method (PCR-RFLP). CDH1 -160 C/A polymorphism was differently distributed between patient and control groups. The A allele of CDH1 -160 C/A polymorphism significantly increased in patients compared to controls. In addition we found that the A allele of this polymorphism might be a potential risk factor for progression of breast cancer in our studied population. Patients with A allele of CDH1 -160 C/A was in higher risk to progress invasive ductal carcinoma. The A allele was also correlated with high grade and stage IV and also with metastatic tumors in studied subjects. The CDH1 -160 C/A polymorphism is correlated with clinicopathologial findings of breast cancer patients. The A allele of CDH1 -160 C/A may be a risk factor for progression of breast cancer in Kurdish patients.
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Affiliation(s)
- Farzaneh Zarei
- Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
| | - Mohammad Nazir Menbari
- Cellular and Molecular Research Center, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Bayazid Ghaderi
- Liver and Digestive Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Internal Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Abdi
- Cellular and Molecular Research Center, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Zakaria Vahabzadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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20
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The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased susceptibility to arsenic-related renal cell carcinoma. Toxicol Appl Pharmacol 2017; 332:1-7. [DOI: 10.1016/j.taap.2017.07.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 07/14/2017] [Accepted: 07/17/2017] [Indexed: 01/31/2023]
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21
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Galimberti S, Bucelli C, Arrigoni E, Baratè C, Grassi S, Ricci F, Guerrini F, Ciabatti E, Fava C, D'Avolio A, Fontanelli G, Cambrin GR, Isidori A, Loscocco F, Caocci G, Greco M, Bocchia M, Aprile L, Gozzini A, Scappini B, Cattaneo D, Scortechini AR, La Nasa G, Bosi A, Leoni P, Danesi R, Saglio G, Visani G, Cortelezzi A, Petrini M, Iurlo A, Di Paolo A. The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia. Oncotarget 2017; 8:88021-88033. [PMID: 29152138 PMCID: PMC5675690 DOI: 10.18632/oncotarget.21406] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 08/29/2017] [Indexed: 11/25/2022] Open
Abstract
First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, in contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.
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Affiliation(s)
- Sara Galimberti
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Cristina Bucelli
- Oncohematology Division, IRCCS Ca' Granda, Maggiore Policlinico Hospital Foundation, University of Milan, Milano, Italy
| | - Elena Arrigoni
- Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy
| | - Claudia Baratè
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Susanna Grassi
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.,GeNOMEC, University of Siena, Siena, Italy
| | - Federica Ricci
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Francesca Guerrini
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Elena Ciabatti
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Carmen Fava
- Hematology Division, Ospedale Mauriziano, Torino, Italy
| | - Antonio D'Avolio
- Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Giulia Fontanelli
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Giovanna Rege Cambrin
- Department of Clinical and Biological Sciences, University of Torino, AOU San Luigi Gonzaga, Torino, Italy
| | - Alessandro Isidori
- Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy
| | - Federica Loscocco
- Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy
| | - Giovanni Caocci
- Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | - Marianna Greco
- Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | - Monica Bocchia
- Division of Hematology, Ospedale Le Scotte, University of Siena, Siena, Italy
| | - Lara Aprile
- Division of Hematology, Ospedale Le Scotte, University of Siena, Siena, Italy
| | - Antonella Gozzini
- Division of Hematology, AOU Careggi, University of Florence, Firenze, Italy
| | - Barbara Scappini
- Division of Hematology, AOU Careggi, University of Florence, Firenze, Italy
| | - Daniele Cattaneo
- Oncohematology Division, IRCCS Ca' Granda, Maggiore Policlinico Hospital Foundation, University of Milan, Milano, Italy
| | | | - Giorgio La Nasa
- Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | - Alberto Bosi
- Division of Hematology, AOU Careggi, University of Florence, Firenze, Italy
| | - Pietro Leoni
- Division of Hematology, Marche Polytechnic University, Ancona, Italy
| | - Romano Danesi
- Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy
| | | | - Giuseppe Visani
- Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy
| | - Agostino Cortelezzi
- Oncohematology Division, IRCCS Ca' Granda, Maggiore Policlinico Hospital Foundation, University of Milan, Milano, Italy
| | - Mario Petrini
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Alessandra Iurlo
- Oncohematology Division, IRCCS Ca' Granda, Maggiore Policlinico Hospital Foundation, University of Milan, Milano, Italy
| | - Antonello Di Paolo
- Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy
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22
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Ankathil R. ABCB1 genetic variants in leukemias: current insights into treatment outcomes. Pharmgenomics Pers Med 2017; 10:169-181. [PMID: 28546766 PMCID: PMC5438075 DOI: 10.2147/pgpm.s105208] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Despite improvements in treatment of different types of leukemia, not all patients respond optimally for a particular treatment. Some treatments will work better for some, while being harmful or ineffective for others. This is due to genetic variation in the form of single-nucleotide polymorphisms (SNPs) that affect gene expression or function and cause inherited interindividual differences in the metabolism and disposition of drugs. Drug transporters are one of the determinants governing the pharmacokinetic profile of chemotherapeutic drugs. The ABCB1 transporter gene transports a wide range of drugs, including drugs used in leukemia treatment. Polymorphisms in the ABCB1 gene do affect intrinsic resistance and pharmacokinetics of several drugs used in leukemia treatment protocols and thereby affect the efficacy of treatment and event-free survival. This review focuses on the impact of three commonly occurring SNPs (1236C>T, 2677G>T/A, and 3435C>T) of ABCB1 on treatment response of various types of leukemia. From the literature available, some of the genotypes and haplotypes of these SNPs have been found to be potential determinants of interindividual variability in drug disposition and pharmacologic response in different types of leukemia. However, due to inconsistencies in the results observed across the studies, additional studies, considering novel genomic methodologies, comprehensive definition of clinical phenotypes, adequate sample size, and uniformity in all the confounding factors, are warranted.
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Affiliation(s)
- Ravindran Ankathil
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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23
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Rychlik-Sych M, Barańska M, Dudarewicz M, Skrętkowicz J, Żebrowska A, Owczarek J, Waszczykowska E. ABCB1
-Gen-Polymorphismus in einer polnischen Kohorte ist mit Risiko für bullöses Pemphigoid assoziiert. J Dtsch Dermatol Ges 2017; 15:499-506. [DOI: 10.1111/ddg.13182_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 11/10/2016] [Indexed: 11/29/2022]
Affiliation(s)
- Mariola Rychlik-Sych
- Department of Pharmacogenetics, Chair of Biopharmacy; Medical University of Lodz; Łódz´ Polen
| | - Małgorzata Barańska
- Department of Pharmacogenetics, Chair of Biopharmacy; Medical University of Lodz; Łódz´ Polen
| | - Michał Dudarewicz
- Department of Pharmacogenetics, Chair of Biopharmacy; Medical University of Lodz; Łódz´ Polen
| | - Jadwiga Skrętkowicz
- Department of Pharmacogenetics, Chair of Biopharmacy; Medical University of Lodz; Łódz´ Polen
| | - Agnieszka Żebrowska
- Department of Dermatology and Venereology, Chair of Dermatology and Venereology; Medical University of Lodz; Łódz´ Polen
| | - Jacek Owczarek
- Department of Pharmacogenetics, Chair of Biopharmacy; Medical University of Lodz; Łódz´ Polen
| | - Elżbieta Waszczykowska
- Department of Dermatology and Venereology, Chair of Dermatology and Venereology; Medical University of Lodz; Łódz´ Polen
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Rychlik-Sych M, Barańska M, Dudarewicz M, Skrętkowicz J, Żebrowska A, Owczarek J, Waszczykowska E. ABCB1 gene is associated with the risk of bullous pemphigoid in a polish population. J Dtsch Dermatol Ges 2017; 15:499-505. [PMID: 28207188 DOI: 10.1111/ddg.13182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 11/10/2016] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND OBJECTIVES Polymorphisms in the P-glycoprotein-encoding ABCB1 gene may affect the intracellular concentration of xenobiotics, and thus contribute to the development of autoimmune diseases, including bullous pemphigoid (BP). The objective of the present study was to investigate whether there is an association between the C3435T and G2677T/A polymorphisms in the ABCB1 gene and the risk of BP in a Polish population. PATIENTS AND METHODS The study included 71 patients with BP and 156 healthy volunteers. Determination of the C3435T polymorphism was carried out using PCR-RFLP; the G2677T/A polymorphism, using allele-specific PCR. RESULTS While there was no correlation between the C3435T polymorphism and the risk of BP, we did find such an association with respect to the G2677T/A polymorphism. The relative risk of BP was more than five times greater in individuals with the 2677TA genotype (OR = 5.52, p = 0.0063), and more than twice as high in carriers of the 2677TT genotype (OR = 2.40, p = 0.0076). At 2.40 (0.000018), the OR in carriers of the 2677T allele was also increased. The greater prevalence of the 2677GG genotype and the 2677G allele in the control group, as well as the OR < 1.0 (0.22 and 0.33, respectively), suggest a protective role of the 2677G allele with respect to the development of BP. CONCLUSIONS The results of the present study indicate that the G2677T/A polymorphism in the ABCB1 gene may affect the risk of developing BP.
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Affiliation(s)
- Mariola Rychlik-Sych
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódz´, Poland
| | - Małgorzata Barańska
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódz´, Poland
| | - Michał Dudarewicz
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódz´, Poland
| | - Jadwiga Skrętkowicz
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódz´, Poland
| | - Agnieszka Żebrowska
- Department of Dermatology and Venereology, Chair of Dermatology and Venereology, Medical University of Lodz, Łódź, Poland
| | - Jacek Owczarek
- Department of Pharmacogenetics, Chair of Biopharmacy, Medical University of Lodz, Łódz´, Poland
| | - Elżbieta Waszczykowska
- Department of Dermatology and Venereology, Chair of Dermatology and Venereology, Medical University of Lodz, Łódź, Poland
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Jiang ZP, Zhao XL, Takahashi N, Angelini S, Dubashi B, Sun L, Xu P. Trough concentration and ABCG2 polymorphism are better to predict imatinib response in chronic myeloid leukemia: a meta-analysis. Pharmacogenomics 2016; 18:35-56. [PMID: 27991849 DOI: 10.2217/pgs-2016-0103] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM The present study aimed to conduct a series of meta-analyses to investigate the influence of imatinib trough concentration (C0), as well as ABCB1 and ABCG2 polymorphisms, on the clinical response in patients with chronic myeloid leukemia (CML). METHODS A literature search was conducted using the PubMed and Cochrane electronic databases to locate relevant papers from 2003 onward. Then, an initial meta-analysis of 14 studies involving 2184 patients was conducted to understand the effect of imatinib mesylate (IM) C0 on clinical outcome in CML patients. Subsequently, a series of meta-analyses were performed, including up to 23 studies with 2577 patients, on the effect of genetic polymorphisms of ABCB1 and ABCG2 on the clinical response to IM. RESULTS Meta-analysis revealed that patients who achieved a major molecular response (MMR) have a significantly higher IM C0 than those who failed to achieve an MMR. We also found that the patients who achieved a complete cytogenic response (CCyR) have a significantly higher IM C0 than those who did not achieve a CCyR. However, no significant difference in IM C0 was found between the complete molecular response and non-complete molecular response groups. Additional analysis showed that ABCG2 421 variant A allele was significantly associated with a higher rate of MMR and overall response, especially in Asian patients. Meta-analysis did not reveal a correlation between ABCB1 C3435T and C1236T polymorphisms with any clinical response to IM. However, the G2677T/A polymorphism could play a role in IM response in the recessive model. CONCLUSION This meta-analysis demonstrates that there was a significant correlation between the IM trough concentration and clinical responses, especially MMR and CCyR, in CML patients. Furthermore, we found that the probability of successful treatment was correlated with the ABCG2 C421A polymorphism, at least within the Asian population. We failed to determine an association between ABCB1 polymorphisms and IM response, although the G2677T/A polymorphism might be involved. However, further large-scale investigations using more sensitive genotyping methods would be required to confirm this.
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Affiliation(s)
- Zhi-Ping Jiang
- Laboratory of Clinical Pharmacology, Department of Hematology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, People's Republic of China
| | - Xie-Lan Zhao
- Laboratory of Clinical Pharmacology, Department of Hematology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, People's Republic of China
| | - Naoto Takahashi
- Department of Hematology, Nephrology, & Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita city, Akita 010-8543, Japan
| | - Sabrina Angelini
- Department of Pharmacology, University of Bologna, Bologna 40126, Italy
| | - Biswajit Dubashi
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry 605 006, India
| | - Li Sun
- Clinical Pharmacy & Pharmacology Research Institute, the Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan Province 410011, People's Republic of China
| | - Ping Xu
- Clinical Pharmacy & Pharmacology Research Institute, the Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan Province 410011, People's Republic of China
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Neul C, Schaeffeler E, Sparreboom A, Laufer S, Schwab M, Nies AT. Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors. Trends Pharmacol Sci 2016; 37:904-932. [PMID: 27659854 DOI: 10.1016/j.tips.2016.08.003] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 08/18/2016] [Accepted: 08/19/2016] [Indexed: 12/21/2022]
Abstract
Small-molecule inhibitors of tyrosine kinases (TKIs) are the mainstay of treatment for many malignancies and represent novel treatment options for other diseases such as idiopathic pulmonary fibrosis. Twenty-five TKIs are currently FDA-approved and >130 are being evaluated in clinical trials. Increasing evidence suggests that drug exposure of TKIs may significantly contribute to drug resistance, independently from somatic variation of TKI target genes. Membrane transport proteins may limit the amount of TKI reaching the target cells. This review highlights current knowledge on the basic and clinical pharmacology of membrane transporters involved in TKI disposition and their contribution to drug efficacy and adverse drug effects. In addition to non-genetic and epigenetic factors, genetic variants, particularly rare ones, in transporter genes are promising novel factors to explain interindividual variability in the response to TKI therapy.
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Affiliation(s)
- Claudia Neul
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany
| | - Alex Sparreboom
- Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH, USA
| | - Stefan Laufer
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany; Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
| | - Anne T Nies
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany
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Cascorbi I, Werk AN. Advances and challenges in hereditary cancer pharmacogenetics. Expert Opin Drug Metab Toxicol 2016; 13:73-82. [DOI: 10.1080/17425255.2017.1233965] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Ghafouri H, Ghaderi B, Amini S, Nikkhoo B, Abdi M, Hoseini A. Association of ABCB1 and ABCG2 single nucleotide polymorphisms with clinical findings and response to chemotherapy treatments in Kurdish patients with breast cancer. Tumour Biol 2016; 37:7901-7906. [DOI: 10.1007/s13277-015-4679-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 12/16/2015] [Indexed: 12/22/2022] Open
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Jalali C, Ghaderi B, Amini S, Abdi M, Roshani D. Association of XRCC1 Trp194 allele with risk of breast cancer, and Ki67 protein status in breast tumor tissues. Saudi Med J 2016; 37:624-630. [PMID: 27279507 PMCID: PMC4931642 DOI: 10.15537/smj.2016.6.13540] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 04/20/2016] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES To evaluate the role of this polymorphism as a risk factor for breast cancer in Kurdish patients and to investigate the possible association between Arg194Trp x-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms with clinical and histopathological outcomes of patients with breast cancer. METHODS A total of 100 breast cancer patients and 200 cancer-free controls in Kurdish population of Kurdistan state admitted to Tohid Hospital, Sanandaj, Kurdistan, Iran between January 2012 and May 2015 were enrolled in this cross-sectional study. Tissue expression of estrogen receptor (ER), progesteron receptor (PR), human epidermal growth factor receptor 2 (Her2/neu), and Ki67 were evaluated by immunohistochemistry (IHC). The Arg194Trp genotypes were determined by polymerase chain reaction- restriction fragment length polymorphism method. RESULTS Our data showed that the risk for breast cancer increased significantly among the Trp variant of XRCC1. Statistically significant association was found between codon 194 polymorphisms and tissue expression of Ki67. CONCLUSION The Trp allele of codon 194 XRCC1 is a potential risk factor for breast cancer in Kurdish ethnicity. Furthermore, effect of this polymorphism on clinical and histological features of breast cancer was significant.
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Affiliation(s)
- Chiya Jalali
- Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. E-mail.
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