Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F17%3A10362332" target="_blank" >RIV/00216208:11110/17:10362332 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11150/17:10362332 RIV/00216208:11310/17:10362332 RIV/00179906:_____/17:10362332 RIV/00023736:_____/17:00011752

Výsledek na webu

<a href="http://dx.doi.org/10.1186/s13046-017-0523-3" target="_blank" >http://dx.doi.org/10.1186/s13046-017-0523-3</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s13046-017-0523-3" target="_blank" >10.1186/s13046-017-0523-3</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

Popis výsledku v původním jazyce

Background: Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia. Methods: In silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher&apos;s exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression. Results: We observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers.

Název v anglickém jazyce

Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

Popis výsledku anglicky

Background: Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia. Methods: In silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher&apos;s exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression. Results: We observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

<a href="/cs/project/NT13899" target="_blank" >NT13899: SEKVENOVÁNÍ NOVÉ GENERACE JAKO NÁSTROJ PERSONÁLNÍ MEDICÍNY U PACIENTŮ S MYELODYSPLASTICKÝM SYNDROMEM A CHRONICKOU MYELOIDNÍ LEUKÉMIÍ.</a><br>

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Experimental and Clinical Cancer Research

ISSN

1756-9966

e-ISSN

—

Svazek periodika

36

Číslo periodika v rámci svazku

April

Stát vydavatele periodika

IT - Italská republika

Počet stran výsledku

17

Strana od-do

—

Kód UT WoS článku

000399769800001

EID výsledku v databázi Scopus

2-s2.0-85018495486