Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients
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 the...
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| Veröffentlicht in: | Journal of clinical medicine 2022-10, Vol.11 (20), p.6217 |
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| creator | Estrada, Natalia Zamora, Lurdes Ferrer-Marín, Francisca Palomo, Laura García, Olga Vélez, Patricia De la Fuente, Iris Sagüés, Miguel Cabezón, Marta Cortés, Montserrat Vallansot, Rolando Omar Senín-Magán, María Alicia Boqué, Concepción Xicoy, Blanca |
| description | 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. |
| doi_str_mv | 10.3390/jcm11206217 |
| format | Article |
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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.</description><identifier>ISSN: 2077-0383</identifier><identifier>EISSN: 2077-0383</identifier><identifier>DOI: 10.3390/jcm11206217</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Bone marrow ; Clinical medicine ; Drug dosages ; Genes ; Kinases ; Leukemia ; Metabolism ; Mutation ; Patients ; Polypeptides ; Targeted cancer therapy</subject><ispartof>Journal of clinical medicine, 2022-10, Vol.11 (20), p.6217</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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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. 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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.</description><subject>Bone marrow</subject><subject>Clinical medicine</subject><subject>Drug dosages</subject><subject>Genes</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Metabolism</subject><subject>Mutation</subject><subject>Patients</subject><subject>Polypeptides</subject><subject>Targeted cancer therapy</subject><issn>2077-0383</issn><issn>2077-0383</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNpdkduKFDEQQBtRcFn3yR8I-CJIazrJ5PIiDOO6LsyoeHsNuVTvZkwnY9Kt7Hf4w2bYRVbrJQV1cqqK6rqnA35JqcKv9m4aBoI5GcSD7oRgIXpMJX14L3_cndW6xy2kZI076X6va80umDnkhCzMvwASuoAyxZAAfQ7pKkL_fnER8hw8oG-mBJPmikJC6ze788YmqMgkj3Zmnwva5QhuiaagT1APOVVAc0aXU-uQgj1-21yXnIJDuxuIOXi0heU7TMGgj42B5n7SPRpNrHB29552X9-ef9m867cfLi43623vqORzT5kRSo2rkROmjJfEroBYorxiwg9sEMJaainnwlEuvfSCcMYMceNoB8osPe1e33oPi53Au9a7mKgPJUym3Ohsgv63ksK1vso_teKYcSya4PmdoOQfC9RZT6E6iNEkyEvVRBC1Ilwo1tBn_6H7vJTU1jtSkkkhyVH44pZyJddaYPw7zID18cj63pHpH8vCm_E</recordid><startdate>20221021</startdate><enddate>20221021</enddate><creator>Estrada, Natalia</creator><creator>Zamora, Lurdes</creator><creator>Ferrer-Marín, Francisca</creator><creator>Palomo, Laura</creator><creator>García, Olga</creator><creator>Vélez, Patricia</creator><creator>De la Fuente, Iris</creator><creator>Sagüés, Miguel</creator><creator>Cabezón, Marta</creator><creator>Cortés, Montserrat</creator><creator>Vallansot, Rolando Omar</creator><creator>Senín-Magán, María Alicia</creator><creator>Boqué, Concepción</creator><creator>Xicoy, Blanca</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9520-3243</orcidid><orcidid>https://orcid.org/0000-0003-3176-6271</orcidid><orcidid>https://orcid.org/0000-0001-5122-7481</orcidid><orcidid>https://orcid.org/0000-0003-1713-7110</orcidid></search><sort><creationdate>20221021</creationdate><title>Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients</title><author>Estrada, Natalia ; 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| subjects | Bone marrow Clinical medicine Drug dosages Genes Kinases Leukemia Metabolism Mutation Patients Polypeptides Targeted cancer therapy |
| title | Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients |
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