|Year : 2018 | Volume
| Issue : 2 | Page : 185-192
Impact of polymorphisms of TP53 Arg72Pro, excision repair cross-complementing Protein 1 Asn118Asn (C118T) and deletion in Intron 2 of BIM in chronic myeloid leukemia patients on imatinib treatment
Sailaja Kagita1, Sadasivudu Gundeti2, Raghunadharao Digumarti1
1 Department of Medical Oncology, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, Andhra Pradesh, India
2 Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
|Date of Web Publication||20-Jun-2018|
Department of Medical Oncology, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam - 530 053, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Imatinib (IM) results in durable responses in a large number of patients with chronic myeloid leukemia (CML). However, a substantial number develops drug resistance. There could be several reasons for the heterogeneity of response. To survive genotoxic damage induced by IM, BCR-ABL1 can modulate DNA repair mechanisms, cell-cycle checkpoints, and Bcl-2 family members. Hence, we aimed to find out the impact of single-nucleotide polymorphisms mainly TP53Arg72Pro, excision repair cross-complementing protein 1 (ERCC1) Asn118Asn (C118T) and deletion in intron 2 of BIM genes in CML patients and their association with disease progression and treatment outcome. Materials and Methods: In the present study, 174 CML and 174 control samples were analyzed for polymorphisms of TP53Arg72Pro, ERCC1 C118T, and intron 2 deletion in BIM genes using polymerase chain reaction-restriction fragment length polymorphism method. Results: Genotyping of TP53Arg72Pro polymorphism showed a trend toward proline genotype/allele association with younger age (P = 0.031), advanced phase, high BCR-ABL1 expression levels and presence of tyrosine kinase domain (TKD) mutations compared to respective groups. Genotyping of ERCC1 C118T polymorphism showed a significant association of CT genotype and T allele with high BCR-ABL1 levels BIM deletion polymorphism was not observed in the present study (P = 0.030) and presence of TKD mutations (P = 0.013). The 72 proline allele and heterozygous 118CT genotype frequencies were significantly elevated in deceased patients compared to those on IM and other tyrosine kinase inhibitors treatment. Conclusion: our data suggested that proline genotype/allele of TP53Arg72Pro polymorphism possibly leading to inefficient apoptosis and 118CT genotype in ERCC1 gene with possibly less DNA repair efficiency might be responsible for the suboptimal responses to IM and poor survival in CML patients. Deletion in intron 2 of BIM gene was not observed in our study.
Keywords: BIM, chronic myeloid leukemia, ERCC1, imatinib, polymorphism, TP53
|How to cite this article:|
Kagita S, Gundeti S, Digumarti R. Impact of polymorphisms of TP53 Arg72Pro, excision repair cross-complementing Protein 1 Asn118Asn (C118T) and deletion in Intron 2 of BIM in chronic myeloid leukemia patients on imatinib treatment. J Nat Sc Biol Med 2018;9:185-92
|How to cite this URL:|
Kagita S, Gundeti S, Digumarti R. Impact of polymorphisms of TP53 Arg72Pro, excision repair cross-complementing Protein 1 Asn118Asn (C118T) and deletion in Intron 2 of BIM in chronic myeloid leukemia patients on imatinib treatment. J Nat Sc Biol Med [serial online] 2018 [cited 2018 Dec 11];9:185-92. Available from: http://www.jnsbm.org/text.asp?2018/9/2/185/234708
| Introduction|| |
Tyrosine kinase inhibitors (TKIs) have revolutionized cancer therapy and resulted in consistently high response rates. Imatinib (IM) is the first successful targeted drug used for chronic myeloid leukemia (CML) management. IM especially targets the BCR-ABL1 gene and blocks the phosphorylation of downstream signaling pathways. Majority of the patients achieve major responses; however, the response is lost in a substantial group of patients. The reasons for this loss of response could be several. While the main cause appears to be kinase domain mutations in BCR-ABL1. BCR-ABL1 can induce resistance by the modulation of DNA repair mechanisms, cell-cycle checkpoints, and Bcl2 protein family members. In addition, BCR-ABL1 enhances ROS (reactive oxygen species) formation, which may contribute to genomic instability leading to drug resistance. Further studies are needed to understand the basis of response heterogeneity and to uncover the downstream signaling mechanisms of apoptosis and DNA repair that mediated intrinsic resistance to TKIs in CML.
TP53 is a tumor suppressor gene. It plays a crucial role in DNA repair, cell-cycle regulation, induction of apoptosis, and maintenance of genome integrity and cell., TP53 Arg72Pro polymorphism has been extensively studied to determine the risk of development of various cancers. These polymorphisms are typically located within proline-rich domain in exon 4 and encode for either proline (CCC) or arginine (CGC). The arginine (Arg 72) allele induces apoptosis with faster kinetics and suppresses transformation more efficiently than proline (Pro 72) allele whereas proline allele (Pro 72) exhibits a lower apoptotic potential, higher cell-cycle arrest, and higher DNA-repair capacity., This polymorphism was shown to be possibly associated with CML, liver, nasopharyngeal, and esophageal squamous cell carcinomas.
The excision repair cross-complementing protein 1 (ERCC1) is a nuclease rate-limiting protein. It plays a pivotal role in nucleotide excision repair pathway. The ERCC1 forms a heterodimer with xeroderma pigmentosum complementation group F and executes DNA damage recognition and excision of damaged nucleotides induced by ultraviolet and DNA damaging agents. Earlier studies have reported that functional polymorphisms of the ERCC1 may influence mRNA expression levels. These lead to inefficient DNA repair and further predisposes to cancer., A silent polymorphism in exon 4 of ERCC1 (Asn118Asn, C118T, rs11615) has been extensively studied and associated with multiple malignancies.,,, The polymorphic codon encodes for same aspargine but has been associated with a 50% reduction of transcription in codon AAT (TT genotype) compared with codon AAC (CC genotype).
The proapoptotic protein BIM, (also known as BCL2 L11), plays an important role in Bax/Bak-mediated cytochrome c release and apoptosis., In CML patients, BCR-ABL1 gene can modulate the expression as well as posttranslational modification of Bcl2 family members to provide protection from apoptosis., IM activates several proapoptotic BH3 proteins and plays a major role in IM -induced apoptosis of the BCR-ABL1 CML cells. A common 2,903 bp deletion polymorphism in intron 2 of BIM gene resulted in impaired expression of proapoptotic BH3 domain, which is crucial in facilitating apoptosis in response to stress signals. BIM deletion polymorphism in intron 2 was associated with inferior responses to TKI and a shorter progression-free survival (PFS) in TKI-treated cancer patients.,,,
Therefore, single-nucleotide polymorphisms (SNPs) mainly TP53Arg72Pro, ERCC1 C118T, and deletion in intron 2 of BIM genes were studied in IM -treated CML patients to find out their impact on disease progression and prognosis.
| Materials and Methods|| |
The present study includes 174 patients with CML and 174 age- and sex-matched control samples. The study was approved by the Institutional Ethics Committee, and informed consent was obtained from patients participating in the study. Primary CML subjects with confirmed diagnosis based on cytogenetic and reverse transcription-polymerase chain reaction (PCR) analysis were included in this study. Secondary- or therapy-related CML samples were excluded from the study. Blood samples from CML patient were collected from Nizam's Institute of Medical Sciences, Hyderabad, and Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam. Genomic DNA was extracted from blood samples using salting-out method. In the present study, median age at onset of CML was 38 years (range 12–89 years) and a male preponderance was observed with a male-to-female ratio of 1.59:1. Of the 174 patients, 140 were in chronic, 23 in accelerated, and 11 in blast crisis phase. A majority of patients were using IM - target treatment: 62 cases were on standard dose 400 mg, 68 on IM higher doses (600 mg + 800 mg), 16 on other drugs (2nd generation TKIs and TKIs on clinical trials), and 28 patients died [Table 1].
Genotyping of TP53 Arg72Pro, ERCC1 Asn118Asn (C118T) and BIM intron 2 deletion polymorphisms
Primer sequences used for polymorphism analysis were as follows: for TP53 Arg72Pro: 5'-GAA GAC CCA GGT CCA GAT GAA-3', and 5'-GAA GGG ACA GAA GAT AGA CAG G-3'; for ERCC1 C118T: 5'-CATGCCCAGAGGCTTCTCATA-3' and 5'-AGGACCACAGGACACGCAGAC-3', and for BIM deletion in intron 2: 5′-CCACCAATGGAAAAGGTTCA-3′, R: 5′-CTGTCATTTCTCCCCACCAC-3′ for detecting wild-type BIM, and 5′-CCACCAATGGAAAAGGTTCA-3′ and 5′-GGCACAGCCTCTATGGAGAA-3′ for identifying the BIM deletion polymorphism.
TP53 Arg72Pro polymorphism was determined by digesting the PCR amplified products with BstU I restriction enzyme and the resultant genotypes were as follows: Proline (131 bp), Arginine (81 bp and 30 bp), and Pro/Arg (131 bp, 81 bp, and 30 bp) [Figure 1]. ERCC1 C118T polymorphism was determined by digesting the PCR products with BsrD I restriction enzyme. The genotypes obtained are as follows: wild-type C/C (542 bp), heterozygous C/T (542 bp, 367 bp, and 175 bp), and mutant T/T (367 bp and 175 bp) [Figure 2]. BIM deletion in intron 2 polymorphism was determined by the resultant PCR products were as follows: 362 bp for wild-type and 284 bp for deletion [Figure 3].
Prognostic scores such as Sokal, Hasford, and European Treatment Outcome Study (EUTOS) were calculated for all patients using baseline hematological variables. Chi-square and multivariate analysis tests were calculated to test the significance of genotype association with the occurrence of CML and its prognosis. All the P values were two-sided, and the level of significance was taken as P < 0.05.
| Results|| |
Correlation with TP53 Arg72Pro polymorphism
Genotyping results revealed that proline genotype and allele frequencies were slightly increased in CML cases compared to controls (P = 0.562). Females were found to have higher heterozygous pro/arg genotype frequency compared to males (56.71%, 47.66%).
Younger patients (<30 years) were found to have significantly increased proline genotype and allele frequencies whereas in older patients, (>30 years) had increased arginine genotype and allele frequencies (P = 0.031).
Proline allele frequency was found to be more in advanced phase (acute and blast crisis) patients compared to those in chronic phase (0.514, 0.471) whereas the frequency of arginine allele was observed to be more in patients in chronic phase compared to those in advanced phases (0.528, 0.485).
When Sokal, Hasford, and EUTOS risk scores were considered, proline genotype and allele frequencies were found to be elevated in Hasford high-risk group of patients (29.54%, 0.511) compared to low- and intermediate-risk groups (20.0%, 0.469). Proline genotype was slightly increased in Sokal and EUTOS high-risk groups compared to respective groups.
With respect to molecular response, the frequency of heterozygous pro/arg genotype and proline allele was increased in patients with higher BCR-ABL1 expression levels (>10% and 0.1%–10%) compared to those with lower levels (<0.1%) (57.74%, 44.77%, and 50.0%) whereas arginine genotype and allele frequency was significantly higher in patients with low BCR-ABL1 levels (<0.1%) compared to those having high expression levels (0.1%–10% and >10%) (33.33%, 29.85%, and 19.71%) (P = 0.394).
When tyrosine mutations were considered, there was increase in proline allele frequency in patients carrying tyrosine kinase domain (TKD) mutations versus patients without TKD mutations (0.544, 0.464). Whereas arginine genotype and allele frequencies were found to be more in patients without TKD mutations versus to those having TKD mutations (28.57%, 17.64%) (P = 0.421). With respect to present status, the frequency of proline allele was increased in deceased patients (0.571) compared to respective groups using IM 400 mg, IM at higher doses, and other TKIs (0.5, 0.441, and 0.406) [Table 2].
No significant difference was observed with respect to combined genotypes of TP53 Arg72Pro polymorphism either in cases or controls, patients with or without TKD mutations and with low or high BCR-ABL1 expression levels [Table 3].
|Table 3: Distribution of genotype combinations of TP53 Arg72Pro polymorphism|
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Correlation with ERCCC1 C118T polymorphism
Genotyping results presented no significant association between cases and controls with respect to ERCC1 codon 118 genotypes (P = 0.467). No variation was found with gender and age at onset of disease. TT genotype frequency was slightly higher in advanced phase patients (20.58%) whereas CC genotype increased in chronic phase patients (30.71%) (P = 0.637). No association was found with either of the Sokal, Hasford, or EUTOS risk groups.
When molecular response was considered, heterozygous CT genotype frequency significantly elevated in patients with higher BCR-ABL1 expression levels (>10%) compared to those harboring lower levels (0.1%–10% and <0.1% levels) (63.38%, 47.76%, 47.22%). Whereas the C allele frequency was observed to be more in patients with low expression levels (P = 0.030).
With respect to TKD mutations, heterozygous CT genotype frequency was found significantly increased in patients having TKD mutations versus patients without TKD mutations (76.47%, 48.57%) (P = 0.013). With respect to present status, CT genotype frequency was found to be significantly elevated in group of deceased (71.42%) compared to those patients using IM 400 mg, IM higher doses, and other medicines (40.32, 57.35, and 62.5) [Table 4].
The ERCC1-118CT genotype was statistically significant in those patients having TKD mutations and conferred 3.517-, 2.838- and 3.441-fold increased risk under codominant, dominant, and over dominant models. The TT genotype conferred 3.114-fold increased risk for those patients having higher BCR-ABL1 levels (>10%) under recessive (odds ratio [OR] 3.114, 95% confidence interval [CI] 1.197–8.103, P = 0.021) model. Whereas CC genotype associated with decreased risk for those patients with lower BCR-ABL1 levels (<10%) under overdominant (OR 0.524, 95% CI 0.282–0.973, P = 0.045) model [Table 5].
|Table 5: Distribution of genotype combinations of ERCC1 C118T polymorphism|
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Correlation with BIM deletion in intron 2 polymorphism
In the present study, BIM deletion polymorphism was not observed either in CML group or in control group.
| Discussion|| |
In CML patients, suboptimal responses to IM therapy might be due to genomic instability, due to BCR-ABL-dependent signaling pathways. To survive genotoxic damage induced by TKI treatment, BCR-ABL1 gene can modulate DNA repair mechanisms, cell-cycle checkpoints, Bcl2 proteins, and enhances ROS generation. Suboptimal responders are a heterogeneous group. Some may respond to continued therapy.
The range of response heterogeneity encompasses significant variations in depth of initial response, duration of response, and overall survival. In the present study, SNPs: TP53Arg72Pro, ERCC1 C118T, and deletion in intron 2 of BIM genes were studied to study their role in CML susceptibility and prognosis as these genes are involved in cell-cycle checkpoint, DNA repair, and apoptosis.
In the present study, TP53 codon 72 genotyping revealed that proline genotype significantly associated with younger patients (<30 years). Camelo Santos et al. found no association between age at the onset of disease and 72 codon polymorphism.
The frequencies of proline genotype and allele showed possible trend toward advanced phase in our study. In initial phase of the disease, relatively low levels of BCR-ABL1 may stimulate moderate resistance to DNA damage-induced apoptosis, whereas at advanced phases high levels of BCR-ABL1 trigger more pronounced resistance. We found higher proline genotype and allele frequencies in patients having high Hasford risk score whereas Camelo Santos et al. reported significant association of arginine genotype with Sokal high risk scores.
Proline genotype was associated with higher BCR-ABL1 expression levels. Earlier also studies reported a possible association between proline allele and poor cytogenetic response., On the contrary, Camelo Santos et al. and Weich et al. found association with arginine genotype with increased risk of response failure to IM treatment (P = 0.021) and higher BCR-ABL1 levels (P = 0.04).,
Arginine genotype and allele frequencies were elevated in patients without TKD mutations. This is the first study to show a correlation between TKD mutations with 72 codon polymorphism. Proline allele increased in TKD mutation carriers and also associated with poor survival in our study. In supporting our data, earlier studies showed association with proline genotype and poor survival., The present study indicates that proline genotype with less apoptotic potential efficiency might not be eliminating the cells with DNA lesions and further leading to drug resistance and poor survival in CML patients.
The ERCC1 C118T is a silent polymorphism with varied gene expression levels can alter the DNA repair capacity. Very few studies are available in the literature that correlating ERCC1 118 codon polymorphism with CML.
Heterozygous CT genotype and T allele were found to be significantly increased in patients with high BCR-ABL1 expression levels (P = 0.030) and patients carrying with TKD mutations (P = 0.013), which indicates that T allele with less repair capability might be associated with resistance to IM treatment in the present study. On contrary Kong et al. reported that patients with TT genotype showed association with major and complete cytogenetic response to IM therapy in CML patients. In support to our data, previous studies also showed that patients with CT and TT genotypes were associated with significantly lower response rates in metastatic colorectal carcinoma patients and nonsmall cell lung cancer with platinum-based chemotherapy.,
Shahnam et al. also reported that there was a trend with T allele association with worse outcome in the Asian population. Lu et al. observed opposite trend with T allele with better outcome in the Caucasian population. In our study, heterozygous CT genotype associated with poor survival. Heterozygous CT genotype with less DNA repair efficiency might lead to drug resistance and poor survival in CML patients.
There are no previous Indian studies between BIM deletion polymorphism and CML. We did not find BIM deletion polymorphism in the present study, as India is one of the South Asian countries, this polymorphism might be absent in our study. BIM deletion polymorphism is restricted to East Asian Ancestry (12.3% carrier frequency), but not in the Africans and Europeans.
| Conclusion|| |
Our data suggested that proline genotype/allele of 72 codon polymorphism in TP53 gene possibly leading to inefficient apoptosis and 118CT genotype in ERCC1 gene with possibly less DNA repair efficiency might be responsible for suboptimal responses to IM and poor survival in CML patients.
The authors would like to thank Tulasi Krishna, MSc Biochemistry, for her assistance in conducting experiments.
Financial support and sponsorship
This work was partially supported by Science and Engineering Research Board (SERB), Startup Research Grant for young Scientists, Government of India.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]