{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:23:11Z","timestamp":1792804991755,"version":"4.5.0"},"reference-count":41,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Novartis Oncology","award":["NF.5.1.2-3d.018\/2014"],"award-info":[{"award-number":["NF.5.1.2-3d.018\/2014"]}]},{"name":"Fundaci\u00f3n Espa\u00f1ola de Hematolog\u00eda y Hemoterapia (FEHH-SEHH)","award":["NF.5.1.2-3d.018\/2014"],"award-info":[{"award-number":["NF.5.1.2-3d.018\/2014"]}],"id":[{"id":"https:\/\/ror.org\/05npya550","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs.<\/jats:p>","DOI":"10.3390\/jcm11206217","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T04:40:36Z","timestamp":1666586436000},"page":"6217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients"],"prefix":"10.3390","volume":"11","author":[{"given":"Natalia","family":"Estrada","sequence":"first","affiliation":[{"name":"Myeloid Neoplasms Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Aut\u00f2noma de Barcelona, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1713-7110","authenticated-orcid":false,"given":"Lurdes","family":"Zamora","sequence":"additional","affiliation":[{"name":"Myeloid Neoplasms Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Aut\u00f2noma de Barcelona, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9520-3243","authenticated-orcid":false,"given":"Francisca","family":"Ferrer-Mar\u00edn","sequence":"additional","affiliation":[{"name":"Hospital General Universitario Morales Meseguer, CIBERER (CB15\/00055), IMIB-Pascual Parrilla, UCAM, 30008 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3176-6271","authenticated-orcid":false,"given":"Laura","family":"Palomo","sequence":"additional","affiliation":[{"name":"MDS Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Aut\u00f2noma de Barcelona, 08916 Badalona, Spain"},{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Myeloid Neoplasms Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Aut\u00f2noma de Barcelona, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"V\u00e9lez","sequence":"additional","affiliation":[{"name":"ICO-Hospital Duran y Reynals, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"De la Fuente","sequence":"additional","affiliation":[{"name":"ICO-Hospital Josep Trueta, 17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Sag\u00fc\u00e9s","sequence":"additional","affiliation":[{"name":"ICO-Hospital Josep Trueta, 17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5122-7481","authenticated-orcid":false,"given":"Marta","family":"Cabez\u00f3n","sequence":"additional","affiliation":[{"name":"Myeloid Neoplasms Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Aut\u00f2noma de Barcelona, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Hospital de Granollers, 08402 Granollers, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolando Omar","family":"Vallansot","sequence":"additional","affiliation":[{"name":"ICO-Tarragona, Hospital Joan XXIII, 43005 Tarragona, 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1182\/asheducation-2017.1.102","article-title":"Treatment-free remission in CML: Who, how, and why?","volume":"1","author":"Mahon","year":"2017","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/s41375-020-0776-2","article-title":"European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia","volume":"34","author":"Hochhaus","year":"2020","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.1002\/cam4.2410","article-title":"Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors","volume":"8","author":"Etienne","year":"2019","journal-title":"Cancer Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.leukres.2013.09.011","article-title":"Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia","volume":"38","author":"Soverini","year":"2014","journal-title":"Leuk. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1124\/pr.110.003533","article-title":"Pharmacogenetics, pharmacogenomics, and individualized medicine","volume":"63","author":"Ma","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1158\/1078-0432.CCR-07-4913","article-title":"Interaction of imatinib with human organic ion carriers","volume":"14","author":"Hu","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1182\/blood-2003-12-4276","article-title":"Active transport of imatinib into and out of cells: Implications for drug resistance","volume":"104","author":"Thomas","year":"2004","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.4161\/cc.3.12.1331","article-title":"Pharmacokinetic Resistance to Imatinib Mesylate: Role of the ABC Drug Pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the Oral Bioavailability of Imatinib","volume":"3","author":"Burger","year":"2004","journal-title":"Cell Cycle"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1200\/JCO.2004.03.050","article-title":"Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients","volume":"22","author":"Peng","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1182\/blood-2008-03-147744","article-title":"Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia","volume":"112","author":"Dulucq","year":"2008","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4750","DOI":"10.1158\/1078-0432.CCR-09-0145","article-title":"Clinical Relevance of a Pharmacogenetic Approach Using Multiple Candidate Genes to Predict Response and Resistance to Imatinib Therapy in Chronic Myeloid Leukemia","volume":"15","author":"Kim","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s12032-010-9456-9","article-title":"Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia","volume":"28","author":"Ni","year":"2011","journal-title":"Med. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.leukres.2010.12.004","article-title":"Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia","volume":"35","author":"Maffioli","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s00280-017-3424-4","article-title":"Molecular study of ABCB1 gene and its correlation with imatinib response in chronic myeloid leukemia","volume":"80","author":"Gharbi","year":"2017","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3324\/haematol.2012.066480","article-title":"Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy","volume":"98","author":"Angelini","year":"2013","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/ejh.12235","article-title":"OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients","volume":"92","author":"Buzaglo","year":"2014","journal-title":"Eur. J. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1179\/1607845414Y.0000000181","article-title":"Relationship between SLCO1B3 and ABCA3 polymorphisms and imatinib response in chronic myeloid leukemia patients","volume":"20","author":"Bueno","year":"2015","journal-title":"Hematology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ejphar.2015.08.034","article-title":"Genetic variations of hOCT1 gene and CYP3A4\/A5 genes and their association with imatinib response in Chronic Myeloid Leukemia","volume":"765","author":"Vaidya","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"780","DOI":"10.4161\/cbt.12.9.17781","article-title":"Single nucleotide polymorphisms of ABCC5 and ABCG1 transporter genes correlate to irinotecan-associated gastrointestinal toxicity in colorectal cancer patients: A DMET microarray profiling study","volume":"12","author":"Arbitrio","year":"2011","journal-title":"Cancer Biol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.2217\/pgs.15.68","article-title":"Predicting paclitaxel-induced neutropenia using the DMET platform","volume":"16","author":"Nieuweboer","year":"2015","journal-title":"Pharmacogenomics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s00280-015-2916-3","article-title":"Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis","volume":"77","author":"Arbitrio","year":"2016","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"54028","DOI":"10.18632\/oncotarget.9927","article-title":"DMET\u2122 (Drug Metabolism Enzymes and Transporters): A pharmacogenomic platform for precision medicine","volume":"7","author":"Arbitrio","year":"2016","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1046\/j.1365-2141.1999.01749.x","article-title":"Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics","volume":"107","author":"Branford","year":"1999","journal-title":"Br. J. Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1182\/blood-2013-05-501569","article-title":"European LeukemiaNet recommendations for the managemen of chronic myeloid leukemia: 2013","volume":"122","author":"Baccarani","year":"2013","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1093\/bioinformatics\/btm025","article-title":"SNPassoc: An R package to perform whole genome association studies","volume":"23","author":"Armengol","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/bioinformatics\/bth457","article-title":"Haploview: Analysis and visualization of LD and haplotype maps","volume":"21","author":"Barrett","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1097\/CEJ.0b013e3282b72093","article-title":"Genetic polymorphisms of metabolic enzymes CYP1A1, CYP2D6, GSTM1 and GSTT1 and leukemia susceptibility","volume":"17","author":"Chen","year":"2008","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22811","DOI":"10.3390\/ijms160922811","article-title":"Pharmacogenetics of BCR\/ABL inhibitors in chronic myeloid leukemia","volume":"16","author":"Polillo","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1056\/NEJMoa1609324","article-title":"(IRIS Investigators). Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia","volume":"376","author":"Hochhaus","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/jhg.2010.98","article-title":"Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia","volume":"55","author":"Takahashi","year":"2010","journal-title":"J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.phrs.2018.02.005","article-title":"Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: A systematic review and meta-analysis","volume":"131","author":"Cargnin","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10038-006-0087-0","article-title":"Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin","volume":"52","author":"Shikata","year":"2017","journal-title":"J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1158\/1078-0432.CCR-10-2250","article-title":"Drug Transporters and Imatinib Treatment: Implications for Clinical Practice","volume":"17","author":"Eechoute","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.cmet.2005.01.002","article-title":"ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation","volume":"1","author":"Kennedy","year":"2005","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19719","DOI":"10.1073\/pnas.1113021108","article-title":"ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter","volume":"108","author":"Tarling","year":"2011","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.exphem.2014.02.006","article-title":"Statins inhibit ABCB1 and ABCG2 drug transporter activity in chronic myeloid leukemia cells and potentiate antileukemic effects of imatinib","volume":"42","author":"Mrowka","year":"2014","journal-title":"Exp. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bandyopadhyay, S., Li, J., Traer, E., Tyner, J.W., Zhou, A., Oh, S.T., and Cheng, J.X. (2017). Cholesterol esterification inhibition and imatinib treatment synergistically inhibit growth of BCR-ABL mutation-independent resistant chronic myelogenous leukemia. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179558"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.phrs.2017.03.011","article-title":"Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia","volume":"120","author":"Harivenkatesh","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1007\/s40262-016-0494-0","article-title":"CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients","volume":"56","author":"Barratt","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41397-018-0050-4","article-title":"An exploratory study by DMET array identifies a germline signature associated with imatinib response in gastrointestinal stromal tumor","volume":"19","author":"Ravegnini","year":"2019","journal-title":"Pharmacogenomics J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1086\/430507","article-title":"Rational Inferences about Departures from Hardy-Weinberg Equilibrium","volume":"76","author":"Pluzhnikov","year":"2005","journal-title":"Am. J. Hum. Genet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/20\/6217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:59:11Z","timestamp":1760144351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/20\/6217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,21]]},"references-count":41,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jcm11206217"],"URL":"https:\/\/doi.org\/10.3390\/jcm11206217","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,21]]}}}