Impact of Variants in the ATIC and ARID5B Genes on Therapeutic Failure with Imatinib in Patients with Chronic Myeloid Leukemia.

Karla Beatriz Cardias Cereja Pantoja,Tereza Cristina De Brito Azevedo,Amanda De Nazaré Cohen Paes,Lui Wallacy Morikawa Souza Vinagre,Natasha Monte,Ana Rosa Sales De Freitas,Rommel Mario Rodríguez Burbano,Maria Clara Da Costa Barros,Ney Pereira Carneiro Dos Santos,Paulo Pimentel De Assumpção,Marianne Rodrigues Fernandes,Darlen Cardoso De Carvalho,Sidney Emanuel Batista Dos Santos

doi:10.3390/genes13020330

Karla Beatriz Cardias Cereja Pantoja, Tereza Cristina De Brito Azevedo + Show 11 more

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https://doi.org/10.3390/genes13020330

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Journal: Genes	Publication Date: Feb 10, 2022
Citations: 4	License type: CC BY 4.0

Affiliation: Universidade Federal do Pará, Humana (United States)

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the BCR-ABL genes. The first-line treatment for CML is imatinib, a tyrosine kinase inhibitor that acts on the BCR-ABL protein. However, even though it is a target-specific drug, about 25% of patients do not respond to this treatment. The resistance mechanisms involved in this process have been investigated and studies have shown that germinal alterations can influence this mechanism. The aim of this work was to investigate 32 polymorphisms in 24 genes of carcinogenic pathway to verify the influence of these genetic variants on the response to treatment with imatinib. Our results demonstrated that individuals with the recessive GG genotype for the rs2372536 variant in the ATIC gene are approximately three times more likely to experience treatment failure with imatinib (p = 0.045, HR = 2.726, 95% CI = 0.9986–7.441), as well as individuals with the TT genotype for the rs10821936 variant in the ARID5B gene, who also have a higher risk for treatment failure with imatinib over time (p = 0.02, HR = 0.4053, IC 95% = 0.1802–0.911). In conclusion, we show that variants in the ATIC and ARIDB5 gene, never screened in previous studies, could potentially influence the therapeutic response to imatinib in patients treated for CML.

Highlights

Chronic myeloid leukemia (CML) has as its main characteristic the reciprocal and balanced translocation of chromosomes 9 and 22 t (9q34 and 22q11), which results in the Philadelphia chromosome and fusion of the BCR-ABL genes [1,2]
Genotype and Imatinib Response-Relative Risk Assessment (OR) Regarding genetic variants, we found no association between responsiveness to therapy at a specific time and the investigated SNPs (Supplementary Table S3)
Time of Treatment Failure (TTF)/Risk Analysis over the Response Time (HR) We investigated the relationship between genetic variants and the variable “time of treatment failure” (TTF) to estimate the risk of treatment failure over time

Summary

Introduction

Chronic myeloid leukemia (CML) has as its main characteristic the reciprocal and balanced translocation of chromosomes 9 and 22 t (9q34 and 22q11), which results in the Philadelphia chromosome and fusion of the BCR-ABL genes [1,2]. Treatment of CML is performed with the tyrosine kinase inhibitor (TKI), imatinib, which acts directly on the BCR-ABL protein by decreasing its intracellular activity and, controlling the carcinogenic environment [5]. Even though this is a target-specific drug, the response to this treatment is variable, about 25% of patients are not responsive to imatinib [4,6]. Genetic variants can alter gene expression and, modulate the interaction of the expressed protein with the drug, making the response inefficient [7,8,9,10]

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