Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia

Abstract

There are a paucity and contradicted data about the impact of concurrent heredity of polymorphic genes and risk of chronic myeloid leukemia (CML). In the present study, the concurrent effects of three polymorphisms affecting the integrity of DNA consist of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp on development of chronic myeloid leukemia were studied. Furthermore, the role of these polymorphisms in clinical and laboratory outcomes of patients was evaluated. In this case-control study, 70 CML patients and 140 healthy individuals were enrolled in the study. The clinical features of patients such as phase of disease and response to treatment and laboratory data before and after treatment with imatinib mesylate were collected. ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp single nucleotide polymorphisms were evaluated by restriction fragment length polymorphism-polymerase chain reaction. The T allele of ABCB1 C3435T, T allele of XRCC1 Arg194Trp, and C allele of ABCG2 C421A polymorphisms were significantly higher in patients than controls. TT genotype of ABCB1 and TT genotype of XRCC1 were associated with higher risk of chronic myeloid leukemia development. CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 were also correlated with a higher risk of CML. Patients with C allele of ABCB1 had poor cytogenetic response, and correlation of CC421 ABCG2/TT3435 ABCB1 diplotype with accelerated phase of CML was significant. Patients with CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 diplotypes might be at higher risk to rapid and severe development of CML and have weaker response to treatments with imatinib.

<em>ABCB1</em> genetic variants in leukemias: current insights into treatment outcomes

“…Studies conducted on Malaysian CML patients had shown no relationship between 3435C>T polymorphism and response to a standard dose of IM 89. In a recent study by Salimizand et al,90 CML patients with C allele of ABCB1 C3435T had poor cytogenetic response and TT3435 ABCB1 diplotype was significantly associated with accelerated phase of CML. This study also indicated that CML patients with TT3435 ABCB1 might be having weaker response to IM therapy.…”

“…It has been reported90 that the ABCB1 2677 G>T/A single nucleotide substitution strongly affects the secondary structure of ABCB1 mRNA. A decrease in P-gp expression could result in higher intracellular concentration of IM.…”

ABCB1 gene is associated with the risk of bullous pemphigoid in a polish population

“…In the present study, we analyzed the effects of the C3435T and G2677T/A polymorphisms in the ABCB1 gene on the risk of developing bullous pemphigoid (BP) in a Polish population. Available data suggests that genetically determined P‐gp polymorphisms may predispose to the development of neoplasms, neurological disorders, and diseases of the gastrointestinal tract .…”

A study of the association of C3435T polymorphism of MDR1 gene and its mRNA expression with the level of daunorubicin accumulation in leukocytes in patients with chronic myeloproliferative diseases

“…1 Krasnoyarsk branch of the «National Research Center for Hematology» Department of Health, Krasnoyarsk, Russia; 2 Federal Research Center Krasnoyarsk Scientific Center, Siberian Branch of RAS, Krasnoyarsk, Russia; 3 Krasnoyarsk City Clinical Hospital №7, Krasnoyarsk, Russia; 4 Regional Clinical Hospital, Krasnoyarsk, Russia; 5 Siberian Federal University, Krasnoyarsk, Russia…”