The Effect of FOXO3a rs4946936 Gene Polymorphism on Imatinib Mesylate Therapy Response in Javanese Race CML patients at Dr. Saiful Anwar General Hospital Malang

Shinta Oktya Wardhani¹*, Hani Susianti², Puji Rahayu³, Yuyun Yueniwati⁴

¹Doctoral Program in Medical Science, Division of Hematology and Oncology,

Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.

²Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine,

Universitas Brawijaya, Malang, 65145, Indonesia.

³Department of Otorhinolaryngology, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.

⁴Department of Radiology, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.

*Corresponding Author E-mail: shinta_oktya.fk@ub.ac.id

ABSTRACT:

Genetic factors are known to play a role in the therapeutic response of several diseases, especially malignancy. In the process of apoptosis, Forkhead O transcription factor sub family 3a (Foxo3a) is involved in mitochondria-related and unrelated processes by triggering the expression of death receptor ligands such as Fas ligands, TNF apoptotic ligands and Bcl-xL, bNIP3, Bim from members of the Bcl2 family. In a study using a cell line, Foxo3a inactivation was shown due to a mutation in the FOXO3a gene, and this inactivation was associated with cancer progression. In addition, failure to induce apoptosis so that cancer cells continue to survive and spread is also the cause of failure to achieve a treatment response. This study aims to determine the role of genetic factors in the form of the FOXO3a rs4946936 gene polymorphism in response to imatinib mesylate therapy. This prospective cohort study was conducted at dr. Saiful Anwar General Hospital between February 2019 and February 2021. The method used for sampling was consecutive sampling. This study was approved by the ethic department of dr. Saiful Anwar General Hospital. Regression test were used to observe the effect of the FOXO3a rs 4946936 gene on the therapeutic response. Our results showed that the CC genotype was more common in the treatment response group, while the TT genotype was more common in the non-treated group. The TC genotype FOXO3a rs4946936 had a 6.96 (p=0.004) times risk of not achieving a major molecular response compared to the CC genotype. The TT genotype had a 17 times risk (p=0.003) of not achieving a major molecular response than the CC genotype. FOXO3a rs4946938 gene polymorphism influenced the response to imatinib mesylate therapy in CML patients. The CC genotype was more likely to achieve a therapeutic response than other genotypes and the T-allele was a susceptibility allele not to achieve a major molecular response.

KEYWORDS: FOX3a, Imatinib genotype, Therapy response.

INTRODUCTION:

Genetic factors are known to play a role in the therapeutic response of several diseases, especially malignancy.¹ Genetic polymorphisms involved in DNA repair and apoptosis are thought to influence the patient's response to cancer treatment, because chemotherapeutic agents cause lethal effects on cancer cells through apoptosis triggered by DNA damage.

The outcome of treatment is determined not only by the severity of the DNA damage due to therapy but also by the ability of the malignant cells to repair DNA damage and initiate apoptosis.²

In the process of apoptosis, Forkhead O transcription factor sub family 3a (Foxo3a) is involved in mitochondria-related and unrelated processes by triggering the expression of death receptor ligands such as Fas ligand, apoptotic ligand TNF and Bcl-xL, bNIP3, Bim from members of the Bcl2.³ family. Foxo3a is also known to play a role in maintaining ROS balance in hematopoietic stem cells.² In addition, the loss of Foxo3a causes accumulation of DNA damage in primitive hematopoietic stem cells and progenitor cells through decreased expression of genes that play a role in repairing oxidative damage.³ Foxo3a stimulates several cellular mechanisms including proliferation, apoptosis, DNA damage, activation of Reactive Oxygen Species (ROS), cell cycle progression and tumorigenesis.^4-6

A lot of evidence showed that the FOXO3a gene is a tumor suppressor gene in cancer. In studies using cell lines, it was shown that Foxo3a inactivation was due to mutations in the FOXO3a gene, and this inactivation was associated with cancer progression.⁵ The loss of function of the FOXO3a gene has also been reported to be associated with cancer therapy resistance.^7-10 The mechanism underlying this resistance was associated with the failure to induce cell cycle arrest and the ability to repair DNA damage that causes disruption of genomic stability leading to tumor cell development. In addition, failure to induce apoptosis so that cancer cells continue to survive and spread was also the cause of failure to achieve a treatment response.^11-13

Imatinib mesylate therapy resistance in a multicenter study in Indonesia in 2015 showed higher results (47.69%) than in Europe (24%).^14,15 In Indonesia, chronic myeloid leukemia (CML) was mostly found in productive age (36 years) while in Europe, many were elderly (64 years old).^14,15 Both of these factor put more burden on the management of CML in Indonesia, especially because the cost of treatment for tyrosine kinase inhibitors (TKI), especially imatinib mesylate, is still quite expensive. This study aims to determine the role of genetic factors in the form of the FOXO3a rs4946936 gene polymorphism in response to imatinib mesylate therapy.

MATERIALS AND METHODS:

Study Design:

A prospective cohort study was conducted at dr. Saiful Anwar General Hospital between February 2019 to February 2021. Consecutive sampling method was used to recruit patients (minimum total of 26 study subjects in each group based on the calculation of the minimum sample according to the estimate that the prevalence of CML is 10-12 per 100,000 population with a minimum margin of error of 0.5% and a confidence level of 95%).¹⁶ Inclusion criteria for this study were LGK patients with positive Bcr-Abl examination results who had received TKI imatinib mesylate therapy for at least 6 months, patient age 18 years at the start of the study, Javanese race for at least 3-generation (parents - grandparents - great-grandparents) who were willing to sign the informed consent. While the exclusion criteria were patients who received drugs that reduce the effectiveness of imatinib mesylate namely erythromycin, verapamil, proton-pump inhibitors and prazosin, patients with chronic obstructive pulmonary disease, patients with rheumatoid arthritis, patients with acute lymphoblastic leukemia, and patients with vitiligo.^17,18 This study was approved by the ethics department of dr. Hospital. Saiful Anwar with ethical number: 400/146/K.3/302/2019. The data were analyzed using SPSS 24 software. In the descriptive sample, different tests were used to draw conclusions. Meanwhile, to find the effect of the FOXO3a rs4946936 gene on the therapeutic response, a regression test was used. The p value of <0.05 was considered significant.

Outcome Measurement:

The variables in our study were FOXO3a gene SNPs rs4946936 genotypes CC, TC and TR measured by PCR-RFLP analysis following the instructions from the manufacturer's manual. Quantification, concentration measurement, DNA purity using nanodropTM one spectrophotometer (Thermo Fisher Scientific Inc, Wilmington USA). DNA sequencing by PCR method using CFX96 Thouch TM Real time PCR (Bio Rad. USA) with primers MyTaq HS Mix, 2X, (Bioline, Meridian BioscienceTM, USA) FOXO3a F : 5'–GGGTCCTGAGAACTTCTGAGT-3' FOXO3a R : 5'- GACATTCTGTAAGACATTCTGCCT-3'. CC, TC and TT genotypes were determined by Restriction Fragment Length Polymorphism (RFLP) using Restriction Enzyme: SfcI (New England Biolabs, USA) according to band markers, TT genotype was marked with a band measuring 224 bp; TC genotypes were indicated by bands measuring 224, 152, and 72 bp; while the CC genotype was characterized by bands measuring 152 and 72 bp.

Outcome of therapeutic response was based on ELN 2020 criteria. Major molecular responses were classified into optimal response (if after 6 months of therapy Bcr-Abl 1%IS) and alert/warning response (if after 6 months of therapy Bcr-Abl >1% - 10% IS). Major molecular response was not achieved if after 6 months of therapy Bcr-Abl > 10% IS.¹⁹ Bcr-Abl was measured by RT PCR method with reagents from Bioneer.

RESULT AND DISCUSSION:

This study included a total of 60 patients who received imatinib mesylate therapy and met the inclusion and exclusion criteria, from the previous 65 patients but 2 of them we were excluded because of a history of using therapy that reduces the effectiveness of imatinib mesylate (proton-pump inhibitor) and not pure Javanese race, one person has Chinese race grandfather and 3 samples failed in the amplification process. Of the 60 subjects, 30(50%) achieved an optimal major molecular response with 18(60%) subjects achieving an optimal major molecular response and 12(40%) subjects achieving a major molecular response that requires caution (Warning).

Table 1. Subject Study Characteristics

Variable Characteristics	Total Patient n=60	SNP Gen FOXO3a rs4946936			p- value
		CC n=21	TC n=29	TT n=10
Age (years)	43 ± 12	44 ± 11.7	42 ± 13	43 ± 14	0.877^a
Sex - Female, n(%) - Male, n(%)	29 (48.3) 31 (51.7)	10 (47.6) 11 (52.4)	14 (48.3) 15 (51.7)	5 (50.0) 5 (50.0)	0.992^c
Clinical Phase -  Chronic phase, n(%) - Acceleration phase, n(%) - Blast crisis phase, n(%)	34 (56.7) 23 (38.3) 3 (5.0)	15 (71.4) 6 (28.6) 0 (0.0)	16 (55.2) 11 (37.9) 2 (6.9)	3 (30.0) 6 (60.0) 1 (10.0)	0.233^c
EUTOS Prognostic Score - Low risk, n(%) - High risk, n(%)	51 (85.0) 9 (15.0)	19 (90.5) 2 (9.5)	25 (86.2) 4 (13.8)	7 (70.0) 3 (30.0)	0.318^c
Blood Sample Result
- Hb (g/dl), mean ± SD	11.7 ± 2.3	12.4 ± 2.2	11.3 ± 2.2	11.5 ± 2.5	0.207^a
- Leucocyte (/uL), mean ± SD	52.389.68 ± 104.285.9	25.698.1 ± 56.533.51	42165.55 ± 94168.6	138092 ± 162617.05	0.013^a*
- Thrombocyte (x1000/uL), median (range)	196(56 – 5314)	204(56 – 496)	190(64 – 5314)	226.5(139 – 678)	0.492^b
-  Blast cells, median (range)	5 (0 – 61)	5 (0 – 20)	3 (0 – 32)	20 (3 – 61)	0.003^b*
- Basophil, median (range)	0.4 (0.0 – 6.0)	0.3(0.0 – 3.8)	0.5 (0.0 – 5.3)	0.9 (0.0 – 6.0)	0.072^b
Splenomegaly - £ Schuffner 4 (S4), n(%) - ³ Schuffner 5 (S5), n(%)	25 (41.7) 35 (58.3)	10 (47.6) 11 (52.4)	11 (37.9) 18 (62.1)	4 (40.0) 6 (60.0)	0.785^c
Major Molecular Respone - Achieved response (BcrAbl £10% IS), n(%) - Not achieved response (Bcr-Abl >10% IS), n(%)	30 (50.0) 30 (50.0)	17 (81.0) 4 (19.0)	11 (37.9) 18 (62.1)	2 (20.0) 8 (80.0)	0.001^c*

Table 2. The effect of FOXO3a rs4946936 gene polymorphism on therapeutic response

Variable	Major Molecular Response				p-value	OR (95% CI OR)
	Achieved Response n=30	Achieved Optimal Response (n =18)	Achieved Alert Response (n =12)	Not-achieved Response n=30
CC (n,%)	17 (56.7)	12 (70)	5(30)	4 (13.3)		1
TC (n,%)	11 (36.7)	6 (55)	5(45)	18 (60.0)	0.004*	6.96 (1.856 – 26.10)
TT (n,%)	2 (6.6)	0	2(100)	8 (26.7)	0.003*	17.0(2.56 – 112.98)
C-Allele (n,%)	45 (75%)	30 (67)	15 (33)	26 (43.3%)		1
T-Allele (n,%)	15 (25%)	6 (40)	9 (60)	34 (56.7%)	<0.001*	4.8 (2.6 – 10.6)

Thirty (50%) Other subjects did not achieve a major molecular response. The data on the characteristics of the research subjects are presented in Table 1.

Our results showed that the CC genotype was more common in the treatment response group, while the TT genotype was more common in the non-treated group. None of the TT genotypes achieved an optimal molecular response. There is an effect of the FOXO3a rs4946936 gene polymorphism on major molecular responses.

The TC genotype FOXO3a rs4946936 had a 6.96 (p=0.004) times risk of not achieving a major molecular response compared to the CC genotype. The TT genotype had a 17 times risk (p=0.003) of not achieved a major molecular response than the CC genotype.

The T-allele is a susceptibility allele for not achieving a therapeutic response with a risk of 4.8 times (p<0.001) greater than the C-allele, as shown in Table 2.

Currently, malignancy therapy is being developed in personalized medicine, so it is very important to include the patient's genetic factors as a consideration to provide appropriate and appropriate therapy. This study seeks to identify markers of genetic factors that can predict response to imatinib mesylate therapy in CML patients. The FOXO3a gene polymorphism was chosen to be a gene that is expected to be a predictive factor based on literature evidence which showed that the FOXO3a gene is a bona fide tumor suppressor so that mutations or changes in this gene are widely associated with cancer incidence and failure to respond to therapy.^7-11

Our study proves that the FOXO3a gene polymorphism rs4946936 had an influence on the non-achieved major molecular response to imatinib mesylate therapy in CML patients. We found that the TT genotype had a greater risk of not achieving a major molecular response than TC and CC. The results of our study were in accordance with the previous research conducted by Zhang. Zhang showed contradictory results in 3 different genotypes, 2 wild/referent homozygous genotypes were associated with achieving therapeutic response, but other genotypes were associated with not achieving therapeutic response.¹⁷Other gene polymorphisms were significantly more prevalent in imatinib mesylate (IM)-resistant patients, while the homozygous referent (TT) genotype and heterogeneous TC variant had no significant effect on treatment response. Similar results were reported by Ni et al in 2011 which showed that homozygous alleles exhibited resistance to imatinib mesylate therapy.^18,19

One of the hallmarks of cancer is the ability to resist apoptosis, and as has been proven in many previous studies, FOXO3a is a gene that regulates transcription factors that activate various physiological and pathological functions by inducing the transcription of various target genes involved in apoptosis, proliferation and cell survival.^20,21,22 FOXO3a has been identified as a direct target of phosphoinositide 3-kinase-mediated signal transduction. In CML, Bcr-Abl also activates the transduction pathway through the same protein that causes inhibition of apoptosis, proliferation and impaired adhesion. These changes increase the proliferation of granulocytes that lead to the clinical picture seen in CRF.²³ Our previous study demonstrated a role for Foxo3a in predicting imatinib mesylate therapy response.²⁴ The result was parallel with several studies which showed that the FOXO3a gene polymorphism rs4946936 affects Foxo3a levels. Kalemci et al confirmed the pathogenesis that explains the results of this study, that the FOXO3a rs4946936 gene polymorphism had a significant effect on the major molecular response of CML patients receiving imatinib mesylate therapy.

Our present study is the first report on the effect of FOXO3a gene polymorphisms on treatment response of imatinib mesylate-treated CML patients in Indonesia. These results could explain the influence of genetic factors on treatment response which can also explain the differences in patient response to therapy in Asia including Indonesia with a higher proportion of T-alleles than the proportion of T alleles in Europe (ALFA data). The findings of this study may in the future serve as a baseline evaluation for predicting response to imatinib mesylate therapy and contribute to the improvement of imatinib mesylate therapy procedures in CML patients, so that failure of imatinib mesylate therapy in patients with the FOXO3a gene polymorphism of the TT genotype can be prevented^{25,26,27,28,29,30}.

There are some limitations in our study including several factors that may contribute to failure to achieve treatment response such as adherence, presence of Bcr-Abl mutations, presence of leukemic stem cells, all of which were not analyzed. The small sample size and cross-sectional method can also lead to false-positive results and may not be sufficient to explain the true relationship so our findings should be studied and interpreted more carefully and if possible, followed by prospective cohort studies.

CONCLUSION:

Our study demonstrated that the single nucleotide polymorphism FOXO3a rs4946936 affected the response to imatinib mesylate therapy in CML patients. Patients with the CC genotype were more likely to achieve a therapeutic response than other genotypes and the T-allele was the susceptibility allele to not achieve a major molecular response. However, these findings require further confirmation from clinical studies with large samples and follow-up patient survival. The functional or biological relevance of this polymorphism also needs to be explained in future research.

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Received on 22.06.2021           Modified on 17.08.2021

Accepted on 21.09.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(5):2250-2254.

DOI: 10.52711/0974-360X.2022.00374