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

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.

MicroRNA‐145‐5p suppresses cell proliferation, migration, and invasion in upper tract urothelial carcinoma by targeting 5‐aminoimidazole‐4‐carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase

“…Shin and Park et al found that the polymorphism of ATIC (347 C > G, rs2372536) might affect the response of patients with osteosarcoma to methotrexate 32 . Karla et al showed that genetic variants of the ATIC gene affected the therapeutic efficacy of imatinib in chronic myeloid leukemia 33 . We used cBioPortal to analyze seven bladder cancer databases and two UTUC databases.…”

“…32 Karla et al showed that genetic variants of the ATIC gene affected the therapeutic efficacy of imatinib in chronic myeloid leukemia. 33 We used cBioPortal to analyze seven bladder cancer databases and two UTUC databases. We found that FN1 had a higher proportion of mutations (4%) than the other six genes, and FN1 in UTUC had three mutation sites (2225 C > T, 889 C > T, and 1852G > A) (Supporting Information: Figure S3).…”

“…46,47 Cisplatin is currently the firstline chemotherapy for UTUC. ATIC is known to be resistant to the chemotherapeutic agents imatinib and tamoxifen, 33,48 but nothing has been reported for cisplatin. Therefore, further clarification on whether ATIC can affect the resistance of UTUC to cisplatin via IFITM1 is required.…”

The Future of Pharmacogenomics Requires New Discoveries and Innovative Education

“…Studying children in the Amazon region of Brazil, authors investigated possible associations between NUDT15 (rs1272632214) and SLC22A1 (rs202220802) gene polymorphisms and response to treatment (BFM 2009 protocol) in acute lymphoid leukemia patients. Another myeloproliferative neoplasm, chronic myeloid leukemia (CML), and its first-line treatment imatinib are investigated by Cereja Pantoja et al, who conducted a large genotype association study on 32 polymorphisms in several carcinogenic genes, revealing interesting results [ 5 ]. To date, many oncological treatments recognize pharmacogenomic therapeutical suggestions.…”

“…Three reviews focused on pharmacogenomics in oncology, psoriasis, and monogenic diabetes [ 6 , 7 , 8 ]. Furthermore, three research studies elucidate molecular aspects [ 9 ], genetic associations in large populations [ 5 ], and in selected ancestries [ 4 ].…”