ALLELES OF SNPS IN REGULATORY REGIONS OF SLC22A4 AND SLC22A5 GENES ARE SIGNIFICANTLY ASSOCIATED WITH STABLE MAJOR MOLECULAR RESPONSE TO IMATINIB FIRST LINE IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Machova Polakova K. 06/11/16; 135192; S436
Dr. Katerina Machova Polakova
Contributions
Contributions
Abstract
Abstract: S436
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall A2
Background
The bioavailability of imatinib (IM) in leukemic cells at a curative concentration is an important pharmacokinetic factor influencing the response to the treatment of chronic myeloid leukemia (CML) with IM. Pharmacogenetics represents a potential source of molecular markers as patients with inherited haplotype associated with the key genes encoding drug transporters, have genetic predisposition to respond optimally or non-optimally. IM transport was confirmed for transporters encoded by some genes from SLC and ABC families.
Aims
The aim of this study was to screen polymorphisms in the promoter regions of selected SLC and ABC genes and to identify SNPs associated with the response to the first line IM therapy of CML patients.
Methods
Using NGS we screened promoters of 15 SLC and 4 ABC genes on testing cohort of 83 CML patients with optimal (n=42) and non-optimal (n=41) response to IM. Patients were treated with 400mg/day of IM during the minimal follow-up of 24 months. SNPs confirmation in SLC22A4 and SLC22A5 promoters were performed by Sanger Sequencing in the validation cohort of 42 patients. Linkage disequilibrium analysis of genotyped SNPs on European population and proxy identification with the regulatory function in SLC22A4 and SLC22A5 non-coding regions were performed using LDlink1.1. The Fisher´s exact probability test and Chi-square test were used for allele frequency analysis. Cumulative achievement of stable major molecular response (MMR) was calculated using XLSTAT. Kaplan-Meier method was applied for event free survival calculation. Events were defined as loss of MMR, loss of cytogenetic response, TKI switch, BCR-ABL1 mutations, death, hematological relapse and progression.
Results
Among 1486 NGS evaluated sequences we identified 95 SNPs. In the merged cohort of patients from testing and validation cohorts (n=125) we revealed significant differences in the frequencies of rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers associated with optimal and non-optimal response, respectively. We found that loci rs460089 and rs2631365 are in highly significant linkage disequilibrium with another 12 regulatory loci (R2= 0.98-1.0; P= 0.0) located in introns of SLC22A4 and SLC22A5 encoding OCTN1 and OCTN2 IM transporters, respectively. Based on the genotypes association analysis with the response to IM we revealed that rs460089-GC genotype carriers had significantly higher probability to achieve stable MMR (P =0.001) and this was enhanced in rs460089-GC_rs2631365-TC genotypes carriers (Figure 1; P = 0.000). Consequently, patients with rs460089-GC genotypes have higher probability to survive without event in contrast to patients with rs460089-GG (P=0.003), when the contrast was higher in patients with rs460089-GC_rs2631365-TC genotypes in comparison to rs460089-GG_rs2631365-TC (P<0.0001).
Conclusion
We found that SNPs rs460089 and rs2631365 may represent important genetic markers for European population of CML patients by predicting response to the IM therapy at the time of diagnosis. Patients with rs460089-GC_rs2631365-TC genotype would likely respond optimally, in contrast, rs460089-GG_rs2631365-TC genotype represents a risk factor for IM failure and disease progression. This risk factor maybe associated with sub-lethal concentration of IM, which may lead to resistant clone development and disease progression. Patients with high-risk genotype rs460089-GG_rs2631365-TC may profit from therapy with tyrosine kinase inhibitors that are independent on OCTN1 and OCTN2 carriers.Supported by the Ministry of Health of Czech Republic, grant IGA MZCR NT/13899 and Charles University Prague, project GAUK/177815
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Pharmacogenetics, SNP
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall A2
Background
The bioavailability of imatinib (IM) in leukemic cells at a curative concentration is an important pharmacokinetic factor influencing the response to the treatment of chronic myeloid leukemia (CML) with IM. Pharmacogenetics represents a potential source of molecular markers as patients with inherited haplotype associated with the key genes encoding drug transporters, have genetic predisposition to respond optimally or non-optimally. IM transport was confirmed for transporters encoded by some genes from SLC and ABC families.
Aims
The aim of this study was to screen polymorphisms in the promoter regions of selected SLC and ABC genes and to identify SNPs associated with the response to the first line IM therapy of CML patients.
Methods
Using NGS we screened promoters of 15 SLC and 4 ABC genes on testing cohort of 83 CML patients with optimal (n=42) and non-optimal (n=41) response to IM. Patients were treated with 400mg/day of IM during the minimal follow-up of 24 months. SNPs confirmation in SLC22A4 and SLC22A5 promoters were performed by Sanger Sequencing in the validation cohort of 42 patients. Linkage disequilibrium analysis of genotyped SNPs on European population and proxy identification with the regulatory function in SLC22A4 and SLC22A5 non-coding regions were performed using LDlink1.1. The Fisher´s exact probability test and Chi-square test were used for allele frequency analysis. Cumulative achievement of stable major molecular response (MMR) was calculated using XLSTAT. Kaplan-Meier method was applied for event free survival calculation. Events were defined as loss of MMR, loss of cytogenetic response, TKI switch, BCR-ABL1 mutations, death, hematological relapse and progression.
Results
Among 1486 NGS evaluated sequences we identified 95 SNPs. In the merged cohort of patients from testing and validation cohorts (n=125) we revealed significant differences in the frequencies of rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers associated with optimal and non-optimal response, respectively. We found that loci rs460089 and rs2631365 are in highly significant linkage disequilibrium with another 12 regulatory loci (R2= 0.98-1.0; P= 0.0) located in introns of SLC22A4 and SLC22A5 encoding OCTN1 and OCTN2 IM transporters, respectively. Based on the genotypes association analysis with the response to IM we revealed that rs460089-GC genotype carriers had significantly higher probability to achieve stable MMR (P =0.001) and this was enhanced in rs460089-GC_rs2631365-TC genotypes carriers (Figure 1; P = 0.000). Consequently, patients with rs460089-GC genotypes have higher probability to survive without event in contrast to patients with rs460089-GG (P=0.003), when the contrast was higher in patients with rs460089-GC_rs2631365-TC genotypes in comparison to rs460089-GG_rs2631365-TC (P<0.0001).
Conclusion
We found that SNPs rs460089 and rs2631365 may represent important genetic markers for European population of CML patients by predicting response to the IM therapy at the time of diagnosis. Patients with rs460089-GC_rs2631365-TC genotype would likely respond optimally, in contrast, rs460089-GG_rs2631365-TC genotype represents a risk factor for IM failure and disease progression. This risk factor maybe associated with sub-lethal concentration of IM, which may lead to resistant clone development and disease progression. Patients with high-risk genotype rs460089-GG_rs2631365-TC may profit from therapy with tyrosine kinase inhibitors that are independent on OCTN1 and OCTN2 carriers.Supported by the Ministry of Health of Czech Republic, grant IGA MZCR NT/13899 and Charles University Prague, project GAUK/177815
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Pharmacogenetics, SNP
Abstract: S436
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall A2
Background
The bioavailability of imatinib (IM) in leukemic cells at a curative concentration is an important pharmacokinetic factor influencing the response to the treatment of chronic myeloid leukemia (CML) with IM. Pharmacogenetics represents a potential source of molecular markers as patients with inherited haplotype associated with the key genes encoding drug transporters, have genetic predisposition to respond optimally or non-optimally. IM transport was confirmed for transporters encoded by some genes from SLC and ABC families.
Aims
The aim of this study was to screen polymorphisms in the promoter regions of selected SLC and ABC genes and to identify SNPs associated with the response to the first line IM therapy of CML patients.
Methods
Using NGS we screened promoters of 15 SLC and 4 ABC genes on testing cohort of 83 CML patients with optimal (n=42) and non-optimal (n=41) response to IM. Patients were treated with 400mg/day of IM during the minimal follow-up of 24 months. SNPs confirmation in SLC22A4 and SLC22A5 promoters were performed by Sanger Sequencing in the validation cohort of 42 patients. Linkage disequilibrium analysis of genotyped SNPs on European population and proxy identification with the regulatory function in SLC22A4 and SLC22A5 non-coding regions were performed using LDlink1.1. The Fisher´s exact probability test and Chi-square test were used for allele frequency analysis. Cumulative achievement of stable major molecular response (MMR) was calculated using XLSTAT. Kaplan-Meier method was applied for event free survival calculation. Events were defined as loss of MMR, loss of cytogenetic response, TKI switch, BCR-ABL1 mutations, death, hematological relapse and progression.
Results
Among 1486 NGS evaluated sequences we identified 95 SNPs. In the merged cohort of patients from testing and validation cohorts (n=125) we revealed significant differences in the frequencies of rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers associated with optimal and non-optimal response, respectively. We found that loci rs460089 and rs2631365 are in highly significant linkage disequilibrium with another 12 regulatory loci (R2= 0.98-1.0; P= 0.0) located in introns of SLC22A4 and SLC22A5 encoding OCTN1 and OCTN2 IM transporters, respectively. Based on the genotypes association analysis with the response to IM we revealed that rs460089-GC genotype carriers had significantly higher probability to achieve stable MMR (P =0.001) and this was enhanced in rs460089-GC_rs2631365-TC genotypes carriers (Figure 1; P = 0.000). Consequently, patients with rs460089-GC genotypes have higher probability to survive without event in contrast to patients with rs460089-GG (P=0.003), when the contrast was higher in patients with rs460089-GC_rs2631365-TC genotypes in comparison to rs460089-GG_rs2631365-TC (P<0.0001).
Conclusion
We found that SNPs rs460089 and rs2631365 may represent important genetic markers for European population of CML patients by predicting response to the IM therapy at the time of diagnosis. Patients with rs460089-GC_rs2631365-TC genotype would likely respond optimally, in contrast, rs460089-GG_rs2631365-TC genotype represents a risk factor for IM failure and disease progression. This risk factor maybe associated with sub-lethal concentration of IM, which may lead to resistant clone development and disease progression. Patients with high-risk genotype rs460089-GG_rs2631365-TC may profit from therapy with tyrosine kinase inhibitors that are independent on OCTN1 and OCTN2 carriers.Supported by the Ministry of Health of Czech Republic, grant IGA MZCR NT/13899 and Charles University Prague, project GAUK/177815
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Pharmacogenetics, SNP
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45
Location: Hall A2
Background
The bioavailability of imatinib (IM) in leukemic cells at a curative concentration is an important pharmacokinetic factor influencing the response to the treatment of chronic myeloid leukemia (CML) with IM. Pharmacogenetics represents a potential source of molecular markers as patients with inherited haplotype associated with the key genes encoding drug transporters, have genetic predisposition to respond optimally or non-optimally. IM transport was confirmed for transporters encoded by some genes from SLC and ABC families.
Aims
The aim of this study was to screen polymorphisms in the promoter regions of selected SLC and ABC genes and to identify SNPs associated with the response to the first line IM therapy of CML patients.
Methods
Using NGS we screened promoters of 15 SLC and 4 ABC genes on testing cohort of 83 CML patients with optimal (n=42) and non-optimal (n=41) response to IM. Patients were treated with 400mg/day of IM during the minimal follow-up of 24 months. SNPs confirmation in SLC22A4 and SLC22A5 promoters were performed by Sanger Sequencing in the validation cohort of 42 patients. Linkage disequilibrium analysis of genotyped SNPs on European population and proxy identification with the regulatory function in SLC22A4 and SLC22A5 non-coding regions were performed using LDlink1.1. The Fisher´s exact probability test and Chi-square test were used for allele frequency analysis. Cumulative achievement of stable major molecular response (MMR) was calculated using XLSTAT. Kaplan-Meier method was applied for event free survival calculation. Events were defined as loss of MMR, loss of cytogenetic response, TKI switch, BCR-ABL1 mutations, death, hematological relapse and progression.
Results
Among 1486 NGS evaluated sequences we identified 95 SNPs. In the merged cohort of patients from testing and validation cohorts (n=125) we revealed significant differences in the frequencies of rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers associated with optimal and non-optimal response, respectively. We found that loci rs460089 and rs2631365 are in highly significant linkage disequilibrium with another 12 regulatory loci (R2= 0.98-1.0; P= 0.0) located in introns of SLC22A4 and SLC22A5 encoding OCTN1 and OCTN2 IM transporters, respectively. Based on the genotypes association analysis with the response to IM we revealed that rs460089-GC genotype carriers had significantly higher probability to achieve stable MMR (P =0.001) and this was enhanced in rs460089-GC_rs2631365-TC genotypes carriers (Figure 1; P = 0.000). Consequently, patients with rs460089-GC genotypes have higher probability to survive without event in contrast to patients with rs460089-GG (P=0.003), when the contrast was higher in patients with rs460089-GC_rs2631365-TC genotypes in comparison to rs460089-GG_rs2631365-TC (P<0.0001).
Conclusion
We found that SNPs rs460089 and rs2631365 may represent important genetic markers for European population of CML patients by predicting response to the IM therapy at the time of diagnosis. Patients with rs460089-GC_rs2631365-TC genotype would likely respond optimally, in contrast, rs460089-GG_rs2631365-TC genotype represents a risk factor for IM failure and disease progression. This risk factor maybe associated with sub-lethal concentration of IM, which may lead to resistant clone development and disease progression. Patients with high-risk genotype rs460089-GG_rs2631365-TC may profit from therapy with tyrosine kinase inhibitors that are independent on OCTN1 and OCTN2 carriers.Supported by the Ministry of Health of Czech Republic, grant IGA MZCR NT/13899 and Charles University Prague, project GAUK/177815
Session topic: Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Pharmacogenetics, SNP
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